PSEN1 (322)

PSEN1 encodes presenilin-1, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. More than 300 mutations in PSEN1 have been reported and mutations in PSEN1 are the most common cause of early onset Alzheimer's disease.

Mutation	Clinical Phenotype	Pathogenicity	Neuropathology	Biological Effect	Genomic Position	Genomic Region	Mutation Type Codon Change	Research Models	Primary Papers
Q15H	Frontotemporal Dementia	FTD : Unclear Pathogenicity	Unknown	Unknown	1330528266	Coding Exon 3	Point, Missense CAG to CAC	0	Koriath et al., 2018
N32N	Alzheimer's Disease, None	AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 4	Point, Silent AAT to AAC	0	Scacchi et al., 2007
R35Q	None, Alzheimer's Disease	AD : Unclear Pathogenicity	Not applicable.	In vitro, decreased Aβ40 and Aβ42 production; moderate increase in the Aβ42/aβ40 ratio.	rs63750592	Coding Exon 4	Point, Missense CGG to CAG	0	Rogaeva et al., 2001
N39Y	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Unknown		Coding Exon 4	Point, Missense AAC to TAC	0	Koriath et al., 2018
D40del (delACG)	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Decreased Aβ42 production and undetectable Aβ40 production in vitro. Does not cause a frame-shift.	rs759538127	Coding Exon 4	Deletion ACG to ---	0	Nicolas et al., 2015
D40del (delGAC)	Alzheimer's Disease, Frontotemporal Dementia	AD : Pathogenic	Unknown; MRI showed progressive cortical atrophy involving the lateral frontal lobes most prominently. Medial temporal lobe structures were also affected. Imaging by PET with florbetapir showed fibrillary Aβ deposits particularly in the frontal lobes.	Decreased Aβ42 and Aβ43 in CSF in one carrier. In cells, increased Aβ42 secretion with no change in Aβ40. In vitro, abrogated Aβ40 production and decreased Aβ42 production.	rs759538127	Coding Exon 4	Deletion GAC to ---	0	Nygaard et al., 2014
R41S	Parkinson's Disease	PD : Unclear Pathogenicity	Unknown, but in one patient, MRI showed moderate frontal cortex atrophy, PiB-PET no amyloid deposition, FDG-PET mild hypometabolism in the lateral temporal lobe. CSF Aβ and tau were normal; phospho-tau elevated.	Unknown.		Coding Exon 4	Point, Missense AGA to AGT	0	Gatto et al., 2020
R42L	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.	3677775281	Coding Exon 4	Point, Missense CGG to CTG	0	Koriath et al., 2018
P49L	Alzheimer's Disease	AD : Unclear Pathogenicity	Neuropathology consistent with AD in a carrier who also had the PSEN1 G183V mutation.	Unknown		Coding Exon 4	Point, Missense CCA to CTA	0	Perrone et al., 2020
E69D	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Increased Aβ42 and Aβ40 in cell assay; Aβ42/Aβ40 ratio unchanged.		Coding Exon 4	Point, Missense GAA to GAT	0	Nicolas et al., 2015
A79V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ40 ratio; decreased Aβ40 in cells. Undetectable production of Aβ40 and drastically reduced production of Aβ42 in vitro.	rs63749824	Coding Exon 4	Point, Missense GCC to GTC	0	Cruts et al., 1998
V82L	Alzheimer's Disease	AD : Pathogenic	Unknown.	In CHO and HEK-293 cells expressing APP695, the mutant presenilin-1 resulted in a slightly lower ratio of secreted Aβ42/Aβ40. In vitro, it reduced both Aβ40 and Aβ42 production, with very little effect on the Aβ42/Aβ40 ratio.	rs63749967	Coding Exon 4	Point, Missense GTG to CTG	0	Campion et al., 1995
I83_M84del (DelIM, ΔI83/M84, ΔI83/ΔM84)	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Accumulation of noncongophilic, Aβ-positive, cotton-wool plaques in brain parenchyma. Widespread cerebral amyloid angiopathy, neurofibrillary tangles, and neuropil threads.	Hexanucleotide deletion resulting in deletion of two amino acids (I and M). Cultured cells expressing mutant PSEN1 have an elevated Aβ42/Aβ40 ratio compared with cells transfected with wild-type PSEN1. In vitro, Aβ40 production is undetectable and Aβ42 production greatly reduced.	rs63750307	Coding Exon 4	Deletion ATC.ATG to ---.---	0	Houlden et al., 2000; Steiner et al., 2001
I83T	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; MRI showed bilateral atrophy, especially in the parietal and temporal lobes in one case, and frontal and temporal atrophy in another.	Unknown; predicted probably damaging in silico.		Coding Exon 4	Point, Missense ATC to ACC	0	Achouri-Rassas et al., 2015
M84T	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD. Severe CAA, no Lewy bodies observed.	Unknown.		Coding Exon 4	Point, Missense ATG to ACG	0	Lanoiselée et al., 2017
M84V	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in 2 cases. MRI showed cortical and cerebellar atrophy in 2 cases; frontal and temporal lobe atrophy in a third case.	Increased Aβ42 and Aβ42/Aβ40 ratio in cells; predicted to be deleterious by PolyPhen and MutationTaster.		Coding Exon 4	Point, Missense ATG to GTG	0	Hooli et al., 2014
L85P	Myoclonus, Spastic Paraparesis, Parkinsonism, Alzheimer's Disease, Corticobasal Syndrome	AD : Pathogenic, Corticobasal Syndrome : Pathogenic	Neuropathological examination was not available. SPECT and PET showed bilateral hypoperfusion and hypometabolism in the occipital and temporal lobes.	Increased Aβ42/Aβ40 ratio; increased Aβ42 in transfected cells. In vitro, decreased Aβ42 production and abrogated Aβ40 production.	rs63750599	Coding Exon 4	Point, Missense CTC to CCC	0	Ataka et al., 2004
P88H	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown		Coding Exon 4	Point, Missense CCT to CAT	0	Lanoiselée et al., 2017
P88L	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI showed generalized cortical atrophy.	Increased ratio of Aβ42,43/Aβ40 and generation of Aβ45 and Aβ46.		Coding Exon 4	Point, Missense CCT to CTT	0	Liu et al., 2017
V89L (G>T)	Alzheimer's Disease	AD : Pathogenic	Neurofibrillary tangles and neuritic plaques with dystrophic neurites corresponding to stage VI of Braak and Braak. Plaques abundant in the hippocampus, amygdala, and neocortex. Tangles abundant in the neocortex and hippocampus. Some amyloid angiopathy in cortical vessels. Moderate cortical atrophy and enlarged ventricles.	Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.	rs63750815	Coding Exon 4	Point, Missense GTG to TTG	0	Queralt et al., 2002
V89L (G>C)	Alzheimer's Disease	AD : Pathogenic	Typical Alzheimer's disease pathology.	In vitro, decreased production of Aβ40 and Aβ42; increased Aβ42/Aβ40 ratio. In silico, predicted to be deleterious by SIFT and probably damaging by PolyPhen-2.		Coding Exon 4	Point, Missense GTG to CTG	0	Liu et al., 2017
C92S	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increases Aβ42 secretion from mammalian cells and from fibroblasts cultured from a mutation carrier. Elevated Aβ42/Aβ40 ratio. In vitro, abolished Aβ40 production and drastically reduced Aβ42 production.	rs63751141	Coding Exon 4	Point, Missense TGC to TCC	0	Tedde et al., 2003
V94M	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Decreased Aβ42 and Aβ40 production, but unchanged Aβ42/Aβ40 ratio, in vitro.	rs63750831	Coding Exon 4	Point, Missense GTG to ATG	0	Arango et al., 2001
V96F	Alzheimer's Disease	AD : Pathogenic	Unknown.	In vitro, decreased Aβ42 and Aβ40 production; decreased autoproteolytic endopeptidase activity. In cultured cells, increased Aβ42/Aβ40 ratio. In silico, classified as damaging (PolyPhen) or tolerated (SIFT).	rs63750601	Coding Exon 4	Point, Missense GTC to TTC	0	Kamino et al., 1996
V97L	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI from two mutation carriers showed enlarged lateral ventricles and atrophy of the cerebral cortex, especially the temporal lobes.	Elevated intracellular and extracellular Aβ42 compared to mock-transfected cells and those expressing wild-type PSEN1. In vitro, slight decrease in Aβ42 and Aβ40 production.	rs63750852	Coding Exon 4	Point, Missense GTG to TTG	0	Jia et al., 2005
T99A	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but MRI showed atrophy of the parietal and frontal lobes.	Decreased Aβ42, and particularly Aβ40, in vitro. Increased Aβ42/Aβ40 ratio in assay using isolated proteins and in cultured cells. Predicted probably damaging using in silico algorithms (SIFT, Polyphen2).		Coding Exon 4	Point, Missense ACC to GCC	0	Ikeda et al., 2013
V103G	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Unknown, but predicted structural effect and predicted damaging by in silico algorithms (PolyPhen, SIFT, MutationTaster, CADD).		Coding Exon 4	Point, Missense GTC to GGC	0	Gao et al., 2019
F105C	Alzheimer's Disease	AD : Pathogenic	Unknown; neuroimaging showed enlarged ventricles and atrophy in the hippocampus and frontotemporal regions.	Unknown; predicted damaging in silico.		Coding Exon 4	Point, Missense TTT to TGT	0	Jiao et al., 2014; Deng et al., 2014
F105I	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased Aβ42, and particularly Aβ40, production in vitro, resulting in increased Aβ42/Aβ40 ratio.	rs63750325	Coding Exon 4	Point, Missense TTT to ATT	0	Raux et al., 2005
F105L	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including numerous neurofibrillary tangles and senile plaques in the hippocampus with scattered plaques in the cortex.	Unknown.	rs63750321	Coding Exon 4	Point, Missense TTT to TTG	0	Finckh et al., 2000
F105V	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown; predicted probably damaging in silico.		Coding Exon 4	Point, Missense TTT to GTT	0	Gómez-Tortosa et al., 2010
R108Q	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	In cell assay, increased Aβ42 and Aβ40; in vitro, decreased Aβ42 production and undetectable Aβ40 production.	rs200646139	Coding Exon 4	Point, Missense CGG to CAG	0	Dobricic et al., 2012
G111V	Alzheimer's Disease	AD : Pathogenic	Unknown, but an MRI scan of one case revealed bilateral hippocampal atrophy.	Reduced Aβ40, unchanged Aβ42, and elevated Aβ42/Aβ40 ratio in transfected cells. In silico analyses (PANTHER, Mutation Taster, and PolyPhen-2) predict probably pathogenic.		Coding Exon 4	Point, Missense GGG to GTG	0	Qiu et al., 2020
G111W	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown		Coding Exon 4	Point, Missense GGG to TGG	0	Lanoiselée et al., 2017
L113_I114insT (Intron4, p.113+1delG, splice5, InsTAC)	Myoclonus, Myoclonic seizure, Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including neuron loss in the hippocampus and entorhinal cortex, neuritic plaques and neurofibrillary tangles in the hippocampus, and amyloid angiopathy, particularly evident in the cerebellum.	Deletion of a G in splice donor site of intron 4 produces three aberrant transcripts. Increased Aβ42 and Aβ42/Aβ40; reduced Aβ40 and Aβ38 production in patient brain membranes. In iPSC-derived neurons, increased Aβ42/Aβ40, Aβ42/Aβ38, and Aβ43/Aβ40 ratios, while decreased Aβ38/Aβ40. Also, increased BACE1–BACE2 products (Aβ19/20) and BACE1–BACE1/BACE2 products (Aβ34).	rs63751475	Both Intron 4	Insertion/Deletion G to -	0	Tysoe et al., 1998; De Jonghe et al., 1999
L113P	Frontotemporal Dementia	FTD : Pathogenic, Possible AD : Pathogenic	AD-like plaques and tangles; CT scans showed predominant frontotemporal atrophy and SPECT showed hypoperfusion including the frontal lobes.	Unknown.	rs63751399	Coding Exon 4	Point, Missense CTA to CCA	0	Raux et al., 2000
L113Q	Alzheimer's Disease	AD : Pathogenic	Neuritic plaques (Braak stage C); Neurofibrillary tangles (stage VI); Severe amyloid angiopathy.	Decreased Aβ40 production in vitro; increased Aβ42/Aβ40 ratio.	rs63751399	Coding Exon 4	Point, Missense CTA to CAA	0	Finckh et al., 2005
Y115C	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42:Aβ40 ratio in cells and in vitro. In cells, increased Aβ42 secretion; in vitro, decreased Aβ42, and especially Aβ40, production. Also, disruption of lysosome function and autophagy via accumulation of APP β-C-terminal fragments.	rs63750450	Coding Exon 5	Point, Missense TAT to TGT	0	Cruts et al., 1998
Y115D	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Unknown.	rs63749962	Coding Exon 5	Point, Missense TAT to GAT	0
Y115H	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ40, Aβ42/Aβ38, and Aβ43/Aβ40 ratios, while leaving Aβ38/Aβ40 unchanged, in iPSCs. Reduced production of Aβ40 and Aβ38 in vitro; decreased intracelluar Aβ40. Suppressed Aβ production by wild-type PSEN1.	rs63749962	Coding Exon 5	Point, Missense TAT to CAT	0	Campion et al., 1995
T116I	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI and FDG-PET showed atrophy and hypometabolism in temporal and parietal regions.	Unknown, but predicted to be damaging and disruptive of 3D conformation by several in silico analyses (PolyPhen2, PROVEAN, ExPASY, Raptor X).	rs63750730	Coding Exon 5	Point, Missense ACC to ATC	0	La Bella et al., 2004
T116N	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.	rs63750730	Coding Exon 5	Point, Missense ACC to AAC	0	Romero et al., 1999
T116R	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown.		Coding Exon 5	Point, Missense	0	Mann et al., 2001
T116S; P117T	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in biopsies from two individuals.	Unknown. In silico predictions mixed: deleterious (PolyPhen2, SIFT, PROVEAN); uncertain significance (Mutation Taster 2); medium effect (Mutation Assessor); T116S neutral and P117T pathogenic (PredictSNP).		Coding Exon 5	Insertion/Deletion ACC CCA to TCT ACA	0	Blanco et al., 2019
P117A	Alzheimer's Disease, Ataxia	AD : Pathogenic	Unknown.	Increased Aβ42/Aβ total ratio.		Coding Exon 5	Point, Missense CCA to GCA	0	Anheim et al., 2007
P117L	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD. Unusually high amyloid burden, especially in the molecular layer of the cerebellum and in cerebellar vessels.	In vitro, mutant PSEN1 increases Aβ42, inhibits neurite outgrowth and neurofilament assembly, increases cell-cycle arrest, and decreases neuronal differentiation of progenitor cells.	rs63749805	Coding Exon 5	Point, Missense CCA to CTA	1	Wisniewski et al., 1998
P117Q	Alzheimer's Disease	AD : Pathogenic	Unknown, but CSF biomarkers (Aβ42, tau, and phospho-tau) were in the AD pathological range in one case.	Unknown		Coding Exon 5	Point, Missense CCA to CAA	0	Lanoiselée et al., 2017
P117R	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42/Aβ40 ratio; increased Aβ42; increased Aβ40; Affects on cell cycle in immortalized patient lymphocytes.	rs63749805	Coding Exon 5	Point, Missense CCA to CGA	0	Zekanowski et al., 2003
P117S	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD according to CERAD criteria; Neuronal loss estimated to be greater than 70 percent in one brain; extensive loss of white matter; active gliosis throughout the brain; Lewy bodies.	Unchanged total Aβ; Increased relative secretion of Aβ42 by N2a cells and skin fibroblasts from a mutation carrier; Reduced neurite outgrowth in N2a cells compared to cells expressing wild-type PSEN1.	rs63750550	Coding Exon 5	Point, Missense CCA to TCA	0	Dowjat et al., 2004
T119I	Alzheimer's Disease	AD : Pathogenic	Unknown, but in 3 cases, PiB-PET revealed amyloid in frontal, parietal, and temporal regions, and PET-FDG showed hypometabolism in 3 patients including parietal lobe, precuneus, anterior cingulate, dorsal frontal lobe, and temporal lobe. MRI showed atrophy in frontal, parietal, and temporal cortices. CSF Aβ42 was reduced in one case and CSF phospho-tau elevated in another.	Unknown, but most in silico analyses predict it to be damaging, as do structural data. CADD-PHRED score = 24.		Coding Exon 5	Point, Missense ACA to ATA	0	Itzcovich et al., 2019; Giau et al., 2019
E120D (A>C)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased Aβ42, and particularly Aβ40, production in vitro, resulting in an increased Aβ42/Aβ40 ratio.	rs63751272	Coding Exon 5	Point, Missense GAA to GAC	0	Poorkaj et al., 1998
E120D (A>T)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased Aβ42, and particularly Aβ40, production in vitro, resulting in increased Aβ42/Aβ40 ratio.	rs63751272	Coding Exon 5	Point, Missense GAA to GAT	0	Reznik-Wolf et al., 1996
E120G	Alzheimer's Disease	AD : Pathogenic	Frequent amyloid plaques and neurofibrillary tangles; Severe amyloid angiopathy.	Decreased Aβ38 and Aβ40 production and Aβ38/Aβ42 ratio in patient brain sample. Increased Aβ42/Aβ40 in cells. Predicted probably damaging in silico.		Coding Exon 5	Point, Missense GAA to GGA	0	Lladó et al., 2009; Gómez-Tortosa et al., 2010
E120K	Spastic Paraparesis, Parkinsonism, Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ total ratio and extracellular Aβ in cells; reduced Aβ40 and Aβ42 production in vitro; increased Aβ42/Aβ40 ratio in vitro.	rs63750800	Coding Exon 5	Point, Missense GAA to AAA	0	Hutton et al., 1996
T122A	Frontotemporal Dementia	FTD : Pathogenic	Unknown	Unknown		Coding Exon 5	Point, Missense ACC to GCC	0	Koriath et al., 2018
E123K	Alzheimer's Disease	AD : Pathogenic	Unknown, but in 2 cases, MRI showed atrophy in the medial temporal lobes, and PET showed hypoperfusion in the temporal and parietal lobes.	Decreased Aβ40 and Aβ42 production, and an elevated Aβ42/Aβ40 ratio in vitro. Mutation site not conserved between PSEN1 and PSEN2	rs63750378	Coding Exon 5	Point, Missense GAG to AAG	0	Yasuda et al., 1999
Q127_R128del(CAGA);InsG(G)	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42 and decreased Aβ40 secreted from cells, resulting in increased Aβ42/Aβ40 ratio. However, earlier cell-based results suggested no effect on Aβ40 and Aβ42 levels.		Coding Exon 5	Insertion/Deletion CAGAGA to GGA	0	Hsu et al., 2018
H131R	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but PiB-PET showed extensive cortical and striatal amyloid deposition in one patient. Also, FDG-PET showed hypometabolism in precuneus and bilateral temporo-parietal region and reduced blood flow in parietal and temporal lobes. In two patients, MRI showed parietal and temporal atrophy.	Increased Aβ42/Aβ40 ratio in vitro. Also, abrogated pH-sensitivity of Aβ peptide generation in vitro. In silico algorithms predicted benign (Polyphen) and damaging (SIFT).		Coding Exon 5	Point, Missense CAC to CGC	0	Ikeda et al., 2013
S132A	Dementia with Lewy Bodies, Myoclonus	AD : Pathogenic, DLB : Pathogenic	Neuropathology consistent with AD, with severe neocortical Lewy body disease (one case).	Unknown, but in silico algorithms predict the mutation to be probably damaging by Polyphen and “neutral” by Provean. Site is conserved between PSENs.	rs200937800	Coding Exon 5	Point, Missense TCA to GCA	0	Ryan et al., 2016
L134R	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI of the Turkish proband showed atrophy of the cerebrum and cerebellum.	Decreased Aβ42, and abrogated Aβ40, production in vitro. Predicted probably damaging in silico.		Coding Exon 5	Point, Missense CTG to CGG	0	Lohmann et al., 2012
N135D	Alzheimer's Disease	AD : Pathogenic	Brain biopsy showed mild loss of neurons and secondary gliosis with multiple neuritic plaques and abundant neurofibrillary tangles.	Increased Aβ42/Aβ40 ratio in cell lines and in vitro; increases intracellular and secreted Aβ42 and decreases Aβ40 in cells; reduces both Aβ42 and Aβ40 production in vitro.	rs63750353	Coding Exon 5	Point, Missense AAT to GAT	0	Crook et al., 1997
N135S	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including widespread neurofibrillary tangles and neuritic plaques. Some cotton-wool plaques; Mild amyloid angiopathy; Corticospinal tract pathology.	Unknown.	rs63751278	Coding Exon 5	Point, Missense AAT to AGT	0	Finckh et al., 2005
N135Y	Alzheimer's Disease	AD : Pathogenic	Postmortem findings consistent with AD.	Reduced levels of secreted Aβ40 and higher Aβ42/Aβ40 ratio.		Coding Exon 5	Point, Missense AAT to TAT	0	Natelson Love et al., 2017
A136G	Alzheimer's Disease	AD : Pathogenic		In vitro assays showed a moderate decrease in both Aβ40 and Aβ42 production, with the Aβ42/Aβ40 ratio remaining roughly similar to wildtype. Neuroblastoma cells carrying the mutation showed enhanced sensitivity to trophic withdrawal. Also, the mutation enhanced PSEN1 cleavage of ER calcium sensor STIM1, resulting in dendritic spine disruption. Polyphen analysis predicted probably damaging; SIFT predicted tolerated.	rs41345849	Coding Exon 5	Point, Missense GCT to GGT	0	Xu et al., 2002
A137T	Frontotemporal Dementia	FTD : Pathogenic	Unknown	Unknown		Coding Exon 5	Point, Missense GCC to ACC	0	Koriath et al., 2018
M139I (G>C)	Alzheimer's Disease	AD : Pathogenic	Possible mislocalization of presenilin-1 protein; co-localization with tangles.	Increased Aβ42/Aβ total ratio.	rs63750522	Coding Exon 5	Point, Missense ATG to ATC	0	Kim et al., 2010
M139I (G>A)	Alzheimer's Disease	AD : Pathogenic	Possible mislocalization of presenilin-1 protein; co-localization with tangles.	Increased Aβ42/Aβ total ratio.	rs63750522	Coding Exon 5	Point, Missense ATG to ATA	0	Boteva et al., 1996
M139K	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown.	rs63751106	Coding Exon 5	Point, Missense ATG to AAG	0	Dumanchin et al., 1998
M139L	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI in two individuals revealed bilateral atrophy in the hippocampus and cerebral cortex.	Aβ40 levels moderately decreased; Aβ42/Aβ40 ratio increased in cultured cells.		Coding Exon 5	Point, Missense ATG to TTG	0	Qiu et al., 2019
M139T	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42/Aβ40 ratio and decreased Aβ38/Aβ42 ratio in in vitro assay using patient brain samples. Increased Aβ42/Aβ total ratio in transfected cells.	rs63751106	Coding Exon 5	Point, Missense ATG to ACG	1	Campion et al., 1995
M139V	Alzheimer's Disease, Atypical Dementia	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ40, Aβ42/Aβ38, Aβ43/Aβ40, and Aβ2-40:Aβ40; decreased Aβ38/Aβ40, Aβ38/Aβ42, Aβ40/Aβ43, and Aβ11-40:Aβ40. Decreases Aβ40 and Aβ38 levels, while increasing Aβ42 and Aβ43 levels. Mutant protein levels were variable in iPSC-derived neurons suggesting protein instability.	rs63751037	Coding Exon 5	Point, Missense ATG to GTG	0	Alzheimer's Disease Collaborative Group, 1995
V142F	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI showed severe cortical atrophy that was most pronounced in frontal and temporal lobes.	Predicted to be pathogenic by MutPred, SNPs&Go, MutationTaster, and SIFT.		Coding Exon 5	Point, Missense GTC to TTC	0	Wang et al., 2018
V142I	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs63751037	Coding Exon 5	Point, Missense GTC to ATC	0	Koriath et al., 2018
I143F	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, but in one case, more widespread distribution of plaques in the temporal sulcus compared with sporadic AD, and lower ratio of Ab40 to Ab42/Ab43 in plaques. Also, accelerated NFT formation and neuronal loss.	Unknown. Conservative amino acid substitution in a residue forming part of the APP-binding pore.	rs63750322	Coding Exon 5	Point, Missense ATT to TTT	0	Rossor et al., 1996; Palmer et al., 1999
I143M	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in one case.	Unknown, but other mutations at this location alter Aβ peptide production and, in wild-type PSEN1, I143 forms part of the substrate-binding pore.	rs63751071	Coding Exon 5	Point, Missense ATT to ATG	0	Heckmann et al., 2002
I143N	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs63750004	Coding Exon 5	Point, Missense ATT to AAT	0	Raux et al., 2005
I143T	Myoclonus, Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ40 ratio. Increased Aβ42 and decreased Aβ40 secretion in cells; decreased Aβ42 and Aβ40 production in vitro.	rs63750004	Coding Exon 5	Point, Missense ATT to ACT	0	Cruts et al., 1995; Rogaeva et al., 2001
I143V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including abundant amyloid plaques and severe neurofibrillary tangle pathology (stage VI Braak and Braak). Amyloid deposits were comprised largely of Aβ42, with little to no Aβ40. There was minimal amyloid angiopathy in vessels.	Increased Aβ42 and Aβ42/Aβ40 ratio in cells and in vitro.		Coding Exon 5	Point, Missense ATT to GTT	0	Gallo et al., 2011
M146I (G>A)	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity.Variable protein levels, consistent with altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments.	rs63750391	Coding Exon 5	Point, Missense ATG to ATA	0	Jørgensen et al., 1996
M146I (G>C)	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in 3 cases, but more involvement of central grey areas, no vascular lesions, and very mild amyloid angiopathy.	Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity. Variability in mutant protein levels, consistent with altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments.	rs63750391	Coding Exon 5	Point, Missense ATG to ATC	0	Gustafson et al., 1998
M146I (G>T)	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity. High degree of variablilty in mutant protein levels, consistent with altered protein stability. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments.	rs63750391	Coding Exon 5	Point, Missense ATG to ATT	0	Rogaeva et al., 2001
M146L (A>C)	Alzheimer's Disease, Pick's disease	AD : Pathogenic	Neuropathology consistent with AD in multiple affected mutation carriers. Pick bodies and Lewy body pathology, as assessed by α-synuclein staining, have been noted in some cases.	Increased Aβ42/Aβ total ratio; increased Aβ42/Aβ40 ratio; increased Aβ42. No change in Aβ38 or Aβ40 levels. Increased tau hyperphosphorylation. Disrupts calcium dynamics and mitochondrial permeability.	rs63750306	Coding Exon 5	Point, Missense ATG to CTG	14	Sherrington et al., 1995; Sorbi et al., 1995; Alzheimer's Disease Collaborative Group, 1995
M146L (A>T)	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD. In one case, Lewy body pathology in the amygdala, cingulate gyrus, and substantia nigra.	Increased Aβ42, Aβ42/Aβ total, Aβ42:Aβ40 in cells and in vitro assays. No significant change in Aβ38 or Aβ40. Impaired calcium dynamics and mitochondrial permeability.	rs63750306	Coding Exon 5	Point, Missense ATG to TTG	0	Mangone et al., 1995; Morelli et al., 1998
M146V	Alzheimer's Disease, Frontotemporal Dementia	AD : Pathogenic, FTD : Unclear Pathogenicity	Variable: Neuropathology consistent with AD in some cases, but also, in at least one case, mixed pathology including frequent Aβ deposits, tangles, and Pick bodies.	Increased Aβ42/Aβ40 ratio; increased Aβ42 and Aβ43; lowers wild-type PSEN1 gene expression. Inhibits store-operated calcium channel activity, associated with loss of dendritic spines. Increases calcineurin activity, impairs trafficking of glutamate AMPA receptors. Disrupts endosomes via accumulation of APP β-CTF.	rs63750306	Coding Exon 5	Point, Missense ATG to GTG	6	Alzheimer's Disease Collaborative Group, 1995
T147I	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown; predicted probably damaging in silico.	rs63750907	Coding Exon 5	Point, Missense ACT to ATT	0	Campion et al., 1999
T147P	Alzheimer's Disease, Ataxia	AD : Pathogenic	Unknown; neuroimaging showed widespread cortical atrophy, as well as atrophy in the medial temporal lobes, with less severe cerebellar atrophy.	Unknown; predicted probably damaging in silico.		Coding Exon 5	Point, Missense ACT to CCT	0	Testi et al., 2014
L150P	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased Aβ42 production and abrogated Aβ40 production in vitro.		Coding Exon 6	Point, Missense CTG to CCG	0	Wallon et al., 2012
L153V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in one case.	Decreased Aβ40 and Aβ42 production in vitro.	rs63751441	Coding Exon 5	Point, Missense CTG to GTG	0	Raux et al., 2000; Janssen et al., 2001
Y154C	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs63751292	Coding Exon 5	Point, Missense TAT to TGT	0	Janssen et al., 2003
Y154N	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Unknown, MRI and SPECT showed atrophy and hypoperfusion in occipito-parietal areas and internal temporal lobe areas, including the hippocampus.	Dramatically decreased Aβ40 and Aβ42 production, as well as decreased endopeptidase activity, in vitro.	rs63750588	Coding Exon 5	Point, Missense TAT to AAT	0	Hattori et al., 2004
Y156F; Y156_R157insIY	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	Neuropathology in one case was consistent with AD, but more widespread and included cotton-wool plaques. FDG-PET in 2 individuals showed hypometabolism starting in posterior temporo-parietal cortex and spreading rapidly to posterior cingulate, primary motor, and frontal association cortices.	Unknown	rs63750631	Coding Exon 5	Insertion TAC to TTT.ATA.TAC	0	Rogaeva et al., 2001; Moretti et al., 2004
R157S	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but one patient had posterior cortical atrophy and mild medial temporal atrophy as assessed by MRI.	In silico analyses predicted the mutation is likely pathogenic: Polyphen 2, probably damaging; SIFT, deleterious; CADD score, 31.	rs201617677	Coding Exon 5	Point, Missense AGG to AGT	0	Jiang et al., 2019
Y159C	Parkinsonism, Alzheimer's Disease	AD : Pathogenic	Unknown, but in one case, MRI revealed diffuse parietal and hippocampal atrophy, and FDG-PET showed severe hypometabolism in bilateral frontoparieto-temporal cortex.	Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerated (SIFT). Cryo-EM suggests structural role in PSEN1-APP interaction. CADD score = 28.3.	rs778630379	Coding Exon 5	TAT to TGT	0	Kim et al., 2020
Y159F	Alzheimer's Disease	AD : Pathogenic	Unknown, but CSF biomarkers suggestive of AD.	Unknown.	rs778630379	Coding Exon 5	Point, Missense TAT to TTT	0	Kerchner and Holbrook, 2012
H163P	Alzheimer's Disease	AD : Unclear Pathogenicity	Brain biopsy of the frontal cortex showed numerous senile plaques and neurofibrillary tangles compatible with a diagnosis of AD. No spongiform changes or abnormal prion proteins were detected.	Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.		Coding Exon 5	Point, Missense CAT to CCT	0	Kim et al., 2012
H163R	Myoclonus, Alzheimer's Disease	AD : Pathogenic	Data are limited, but neuropathology consistent with AD has been observed in at least one case.	Increased Aβ42/Aβ total ratio in COS-1 cells; drastic reduction of Aβ42 and Aβ40 production in vitro. Affects γ-secretase-dependent neurexin processing.	rs63750590	Coding Exon 5	Point, Missense CAT to CGT	1	Campion et al., 1995; Sherrington et al., 1995; Tanahashi et al., 1995
H163Y	Alzheimer's Disease	AD : Pathogenic	Typical AD neuropathology (one case); decreased glucose metabolism in presymptomatic mutation carriers, especially in the thalamus. Widespread brain amyloid (PiB-PET) and shrunken hippocampi.	Decreased CSF Aβ42 and Aβ38 levels. Increased Aβ42/Aβ total ratio when expressed in COS-1 cells co-transfected with APP695, and increased Aβ42 production in an in vitro assay using purified proteins.	rs63749885	Coding Exon 5	Point, Missense CAT to TAT	0	Alzheimer's Disease Collaborative Group, 1995
A164V	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed generalized atrophy of the brain with pronounced involvement of the anterior temporal lobe, including the hippocampus.	Unknown; predicted possibly damaging in silico.		Coding Exon 6	Point, Missense GCC to GTC	0	Roeber et al., 2015
W165C (G>C)	Alzheimer's Disease	AD : Pathogenic	Unknown		rs63751484	Coding Exon 6	Point, Missense TGG to TGC	0	Campion et al., 1999
W165C (G>T) (W161C)	Alzheimer's Disease	AD : Pathogenic	Unknown, MRI showed diffuse cerebral and cerebellar atrophy in one case.	Unknown, but in silico analyses (SIFT and polyphen) predict the mutation is deleterious, probably damaging.		Coding Exon 6	Point, Missense TGG to TGT	0	Syama et al., 2018
W165G	Alzheimer's Disease	AD : Pathogenic	Unknown; but SPECT showed slight decrease in blood flow to parieto-occipital regions and thalamus in one case. Also, EEG alterations, but normal MRI.	In vitro, increased Aβ42 and Aβ42/Aβ40 ratio; reduced Aβ40.	rs63751010	Coding Exon 6	Point, Missense TGG to GGG	0	Higuchi et al., 2000
L166H	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed marked hippocampal atrophy and cortical atrophy, especially in the insula and the peri-insular temporal lobe. SPECT imaging showed bilateral hypometabolism in the parietal and frontal lobes.	Unknown.	rs63750265	Coding Exon 6	Point, Missense CTT to CAT	0	Pantieri et al., 2005
L166P	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	In one individual, numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex; abundant Aβ-positive amyloid cores in the cerebellar cortex. In another, robust amyloid pathology in the striatum and cerebellum, and asymmetric tau pathology in the primary sensorimotor cortex contralateral to the side most affected by spasticity.	Increased Aβ42 and Aβ43, decreased total Aβ production. Normal endoproteolysis. Reduced Notch and N-cadherin cleavage. Disrupts endosomes via accumulation of APP β-CTF. Also, dominant-negative effect on wild-type PSEN1, and inhibition of calcium leak in the ER.	rs63750265	Coding Exon 6	Point, Missense CTT to CCT	4	Moehlmann et al., 2002
L166R	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI in the proband showed cortical atrophy; PET showed parietal hypoperfusion.	Unknown.	rs63750265	Coding Exon 6	Point, Missense CTT to CGT	0	Ezquerra et al., 2000
L166V	Alzheimer's Disease	AD : Pathogenic	SPECT imaging performed four years after symptom onset showed temporoparietal hypoperfusion. Postmortem evaluation revealed neuropathology consistent with AD, including advanced plaques and tangles (CERAD C, Braak stage VI).	Unknown; predicted possibly damaging in silico.		Coding Exon 6	Point, Missense CTT to GTT	0	Sassi et al., 2014
L166del	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed generalized, symmetrical cerebral atrophy, which was most prominent in the medial temporal lobes.	Unknown.	rs63751458	Coding Exon 6	Deletion CTT to ---	0	Knight et al., 2007
I167del (TTAdel)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased Aβ42 production and undetectable production of Aβ40 in vitro. Predicted pathogenic in silico.		Coding Exon 6	Deletion TTA to ---	0	Jiao et al., 2014
I167del (TATdel)	Alzheimer's Disease	AD : Pathogenic	Unknown	Decreased Aβ42 production and undetectable production of Aβ40 in vitro. Predicted pathogenic in silico.	rs63750879	Coding Exon 6	Deletion ATT.ATA to ATA	0	Janssen et al., 2003
I168T	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Decreased Aβ42 production and abrogated Aβ40 production in vitro; predicted possibly damaging in silico.		Coding Exon 6	Point, Missense ATA to ACA	0	Sassi et al., 2014
S169del (ΔS169, Ser169del, ΔS170)	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI of the proband showed generalized cerebral atrophy with enlargement of the ventricles and widening of the sulci.	Decreased Aβ42 and abrogation of Aβ40 production in vitro. No effect on Notch.		Coding Exon 6	Deletion TCA.TCT to TC---T	0	Guo et al., 2010
S169L	Alzheimer's Disease	AD : Pathogenic	Neuropathology typical of AD, but also Aβ deposition in the cerebellum and white matter, as well as numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes, possibly due to errant migration during development.	Unknown, but cryo-EM analysis of the γ-secretase-complex revealed a direct interaction of the wild-type residue with APP.	rs63751210	Coding Exon 6	Point, Missense TCA to TTA	0	Taddei et al., 1998
S169P	Myoclonic seizure, Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including numerous plaques and neurofibrillary tangles, neuritic irregularities, neuronal lipofuscin, and mild astrocytosis.	Increased Aβ42 and moderately decreased Aβ40 production in vitro; increased Aβ42/Aβ40.	rs63750418	Coding Exon 6	Point, Missense TCA to CCA	0	Ezquerra et al., 1999
S170_ L171insY (Leu171Tyr)	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown		Coding Exon 6	Insertion/Deletion --- to TAT	0	Koriath et al., 2018
S170F	Alzheimer's Disease	AD : Pathogenic	Variable: Some cases with typical AD pathology; Extensive Lewy bodies in the substantia nigra and throughout the brain have also been reported. One case had severe cerebellar pathology, including abundant amyloid deposition and loss of Purkinje cells.	Increased Aβ42/Aβ40 ratio in cells and in vitro, but effects on Aβ42 and Aβ40 levels varied between studies. Effects on calcium homeostasis, phospho-tau expression, autophagy, expression of mitochondrial fission and fusion proteins, cell viability, and trophic factor function have also been reported.	rs63750577	Coding Exon 6	Point, Missense TCT to TTT	0	Snider et al., 2005
S170P	Alzheimer's Disease	AD : Pathogenic, Parkinsonism : Pathogenic	In AD case, typical AD tau pathology was reported. In parkinsonism case, MRI revealed hypointensity in the putamen, globus pallidus, and substantia nigra, as well as frontotemporal cortical atrophy. SPECT showed severe nigrostriatal dopaminergic deficit bilaterally, and 18F-FDG PET hypometabolism in striatal and posterior cingulate.	Predicted damaging by Poly-Phen-2 and Mutation Taster	rs63750577	Coding Exon 6	Point, Missense TCT to CCT	0	Irwin et al., 2013; Carecchio et al., 2017
L171P	Alzheimer's Disease	AD : Pathogenic	Unknown	Drastically decreased Aβ42 production and Aβ40 production was undetectable in vitro.	rs63750963	Coding Exon 6	Point, Missense CTA to CCA	0	Ramirez-Dueñas et al., 1998
L173F (G>C)	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI from two affected mutation carriers showed atrophy of the medial temporal lobe. SPECT showed hypoperfusion of the posterior cingulate gyri and other cortical areas.	N2a cells transfected with mutant PSEN1 secreted significantly more Aβ42 than cells expressing wild-type PSEN1. The Aβ42:Aβ40 ratio was also increased.		Coding Exon 6	Point, Missense TTG to TTC	0	Kasuga et al., 2009
L173F (G>T)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown.		Coding Exon 6	Point, Missense TTG to TTT	0	Jin et al., 2012
L173S	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown, predicted to be damaging by 4 in silico analyses. PHRED-CADD score=24.1		Coding Exon 6	Point, Missense TTG to TCG	0	Wang et al., 2019
L173W	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased Aβ40 and increased Aβ42 and the Aβ42/Aβ40 ratio in vitro.	rs63750299	Coding Exon 6	Point, Missense TTG to TGG	0	Campion et al., 1999
L174del	Alzheimer's Disease	AD : Pathogenic	Unknown, proband MRI revealed slight temporal lobe atrophy.	Increased Aβ40, and decreased Aβ42 and Aβ42/Aβ40 in proband's CSF		Coding Exon 6	Deletion CTG to ---	0	Tiedt et al., 2013
L174M	Alzheimer's Disease	AD : Pathogenic, CAA : Pathogenic	Neuropathology consistent with AD and CAA in one case.	Decreased Aβ40 and increased Aβ42/Aβ40 ratio in in vitro experiments. Conservative mutation in third transmembrane domain.	rs63751144	Coding Exon 6	Point, Missense CTG to ATG	0	Bertoli Avella et al., 2002; Tedde et al., 2003
L174R	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in one case. Also, abundant Lewy bodies in amygdala and entorhinal cortex.	Unknown.	rs63751025	Coding Exon 6	Point, Missense CTG to CGG	0	Klünemann et al., 2004
F175del	Myoclonic seizure, Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI and FDG-PET observations, as well as CSF biomarkers, were consistent with AD.	Increased Aβ42 and Aβ39; decreased Aβ40 in cultured cells.		Coding Exon 6	Deletion TTC to ---	0	Vöglein et al., 2019
F175S	Late-onset	AD : Unclear Pathogenicity	Unknown	Unknown	rs63750771	Coding Exon 6	Point, Missense TTC to TCC	0	Colacicco et al., 2002
F176L	Alzheimer's Disease	AD : Unclear Pathogenicity	Neuropathology consistent with AD, notably abundant amyloid plaques and neurofibrillary tangles in the cortex. In fact, the neuropathology in this individual (Auguste D.) defined these structures as hallmarks of AD.	Abrogates Aβ40 production and dramatically reduces Aβ42 production in vitro.		Coding Exon 6	Point, Missense TTT to CTT	0	Müller et al., 2013
F177L	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42 production and Aβ42/Aβ40 ratio in vitro. Little impact on total cleavage activity of γ-secretase.	rs63749911	Coding Exon 6	Point, Missense TTT to CTT	0	Rogaeva et al., 2001
F177S	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Decreased Aβ42 in CSF of one patient.	rs63749806	Coding Exon 6	Point, Missense TTT to TCT	0	Rogaeva et al., 2001
F177V	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI showed global brain atrophy, especially in the temporal region and hippocampus in one patient.	Increased Aβ42 and Aβ42/Aβ40 in transfected cells.		Coding Exon 6	Point, Missense TTT to GTT	0	Gao et al., 2019
S178P	Alzheimer's Disease	AD : Pathogenic	Unknown	Dramatically reduced production of Aβ42 and abrogated production of Aβ40 in vitro.	rs63750155	Coding Exon 6	Point, Missense TCA to CCA	0	Rogaeva et al., 2001
I180N	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown		Coding Exon 6	Point, Missense ATT to AAT	0	Lanoiselée et al., 2017
G183V	Pick's disease	Other Tauopathy : Unclear Pathogenicity	Mixed findings. In one case, severe frontotemporal atrophy; Pick bodies, tau-positive cytoplasmic neuronal inclusions, in the neocortex; A striking absence of extracellular Aβ deposits. Neuropathology was consistent with Pick’s disease. But in double mutation carrier (G138V and P49L), neuropathology consistent with AD.	Increase in Aβ42/Aβ40 ratio in cells and in vitro; reduced production of Aβ40 and Aβ42 in vitro. No effect on Notch cleavage. Generates alternative transcripts mostly degraded by nonsense-mediated decay, but coding for truncated proteins that may cause loss of function. Forms complexes with wild-type PSEN1, possibly suppressing activity.	rs63751068	Coding Exon 6	Point, Missense GGG to GTG	0	Dermaut et al., 2004
E184D	Alzheimer's Disease	AD : Pathogenic, DLB : Pathogenic, PPA : Pathogenic	Neuropathology consistent with AD in three cases. In addition, CAA pathology described in two cases. Also, in two cases, robust Lewy body pathology and, in one of these cases, accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes.	Decreased Aβ40 and Aβ42 production, and increased Aβ42:Aβ40 ratio, as assessed in vitro.	rs63750311	Coding Exon 7	Point, Missense GAA to GAC	0	Yasuda et al., 1997
E184G	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI of one patient revelaed global cortical atrophy.	Increased Aβ42/Aβ40 ratio, with decreased Aβ42 and Aβ40 production in vitro. In silico algorithms predicted the mutation is damaging and causes structural alterations. Also, mutation is near splice site.		Coding Exon 7	Point, Missense GAA to GGA	0	Wallon et al., 2012
V191A	None	AD : Unclear Pathogenicity	Unknown	Decreased Aβ42 secretion in isolated cells, but decrease in Aβ42/Aβ40 did not reach statistical significance.	rs112451138	Coding Exon 7	Point, Missense GTT to GCT	0	Guerreiro et al., 2010
I202F	Alzheimer's Disease	AD : Pathogenic, CAA : Pathogenic	Neuropathology was consistent with AD, with severe CAA, in one case. CAA included included chronic inflammatory infiltrate surrounding some cortical and leptomeningeal blood vessels. Lewy pathology was found in the amygdala.	Decreased Aβ40 and Aβ42 production in vitro. In patient brain membranes, reduced Aβ38 production and Aβ38/Aβ42 ratio; increased Aβ42/Aβ40 ratio.		Coding Exon 7	Point, Missense ATC to TTC	0	Church et al., 2011
W203C	Amyotrophic Lateral Sclerosis	ALS : Unclear Pathogenicity	Unknown	Unknown. In silico analyses predict it to be deleterious (SIFT, PolyPhen2, and Mutation Taster).	1384308168	Coding Exon 7	Point, Missense TGG to TGC	0	Couthouis et al., 2014
F205_G206del;insC	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown		Coding Exon 7	Deletion TTTGGT to T---GT	0	Lanoiselée et al., 2017
G206A	Alzheimer's Disease	AD : Pathogenic	Typical AD neuropathology, including extensive plaques and tangles (Braak stage VI). Cortical atrophy revealed by MRI and temporo-parietal hypometabolism revealed by FDG-PET.	In cells, increased Aβ42; unchanged Aβ40. In assays with isolated proteins, decreased Aβ42 and Aβ40; increased Aβ42/Aβ40 ratio.	rs63750082	Coding Exon 7	Point, Missense GGT to GCT	0	Rogaeva et al., 2001; Athan et al., 2001
G206D	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42 production; reduced interaction with Pen2; disrupted ER calcium homeostasis.	rs63750082	Coding Exon 7	Point, Missense GGT to GAT	0	Raux et al., 2005
G206S	Alzheimer's Disease	AD : Pathogenic	Unknown; bilateral frontotemporal and parietal hypometabolism by PET; diffuse brain atrophy with enlarged ventricles by CT.	Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.	rs63750569	Coding Exon 7	Point, Missense GGT to AGT	0	Rogaeva et al., 2001; Raux et al., 2005
G206V	Alzheimer's Disease	AD : Pathogenic	Unknown; an early MRI of the proband showed mild atrophy of the brain with normal temporal lobes.	Unknown, but in silico analyses predicted it to be deleterious.	rs63750082	Coding Exon 7	Point, Missense GGT to GTT	0	Goldman et al., 2002
G209A	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed global cortical atrophy and FDG-PET revealed widespread bilateral hypometabolism.	Unknown; predicted likely damaging in silico by PolyPhen2, SIFT, and Provean.		Coding Exon 7	Point, Missense GGA to GCA	0	An et al., 2016
G209E	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI revealed global cerebral atrophy, particularly affecting the hippocampus. FDG-PET showed global hypometabolism, particularly affecting the temporal, parietal, and occipital lobes.	Unknown.	rs63750053	Coding Exon 7	Point, Missense GGA to GAA	0	Rogaeva et al., 2001
G209R	Alzheimer's Disease	AD : Pathogenic	Unknown; imaging showed mild brain atrophy in the temporal lobes at early stages and diffuse brain atrophy predominantly in the frontotemporal lobes at advanced stages. Hypoperfusion in the frontotemporal areas at early stages extending to the parieto-occipital areas at advanced stages.	Abrogated Aβ40 production and drastically reduce Aβ42 production in vitro.	rs63749880	Coding Exon 7	Point, Missense GGA to AGA	0	Sugiyama et al., 1999
G209V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, includin cortical atrophy, extensive amyloid plaques and neurofibrillary tangles, and amyloid angiopathy.	Abrogated Aβ40 production and drastically reduced Aβ42 production in vitro. Also, caused incomplete endoproteolytic processing of PSEN1.	rs63750053	Coding Exon 7	Point, Missense GGA to GTA	0	Poorkaj et al., 1998
M210R	Alzheimer's Disease	AD : Pathogenic	Unknown, but levels of AD biomarkers in proband's CSF (Aβ42, tau, phospho-tau) were in the pathological range.	Unknown.		Coding Exon 7	Point, Missense ATG to AGG	0	Lanoiselée et al., 2017
S212Y	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including neurofibrillary tangles (Braak stage VI) and frequent neuritic plaques. Severe amyloid angiopathy was noted in the cerebellum and occipital cortex, and α-synuclein pathology was detected in the amygdala.	Increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio in cells; dramatically decreased Aβ42 and abrogated Aβ40 production in vitro.		Coding Exon 7	Point, Missense TCC to TAC	0	Ringman et al., 2011
I213F	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ40 and Aβ42 secretion, and increased Aβ42/Aβ40 ratio in transfected cells.	rs63750861	Coding Exon 7	Point, Missense ATT to TTT	0	Zekanowski et al., 2003
I213L	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ40 and Aβ42 production, and an increase in the Aβ42:Aβ40 ratio as assessed in vitro.	rs63750861	Coding Exon 7	Point, Missense ATT to CTT	0	Rogaeva et al., 2001
I213T	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased short (Aβ38, Aβ40, and Aβ42), and increased long (Aβ43, Aβ45, Aβ46+) Aβ peptides in cell lysates and knockin mouse brains. Increased Aβ42/Aβ40 ratio, and decreased Aβ38/Aβ42 and Aβ40/Aβ43 ratios. Also inhibits neuroprotection by trophic factors and impairs angiogenesis in KI mice.	rs63751039	Coding Exon 7	Point, Missense ATT to ACT	0	Kamino et al., 1996
H214D	Alzheimer's Disease	AD : Pathogenic	Unknown	Decreased production of both Aβ40 and Aβ42 in vitro; increased Aβ42/Aβ40 ratio.		Coding Exon 7	Point, Missense CAC to GAC	0	Clarimón et al., 2008; Guerreiro et al., 2010
H214N	Alzheimer's Disease	AD : Pathogenic	Unknown; CT scan showed diffuse cerebral atrophy more pronounced in medial temporal lobes.	Unknown; predicted probably damaging in silico.		Coding Exon 7	Point, Missense CAC to AAC	0	Piccoli et al., 2016
H214R	Alzheimer's Disease	AD : Pathogenic	Unknown, but in one case, MRI showed mild white matter demyelination of the frontal and parietal lobes, with no apparent atrophy of the cerebral cortex or hippocampus.	Unknown, but six in silico algorithms predicted it is deleterious.		Coding Exon 7	Point, Missense CAC to CGC	0	Li et al., 2019
H214Y	Alzheimer's Disease	AD : Pathogenic	Unknown; imaging showed global cortical atrophy with marked frontotemporal atrophy and white-matter lesions.	Unknown; predicted possibly damaging in silico.	rs63751003	Coding Exon 7	Point, Missense CAC to TAC	0	Raux et al., 2005
G217D	Parkinsonism, Alzheimer's Disease	AD : Pathogenic	Cotton wool plaques in the cortex, caudate nucleus, putamen, claustrum, thalamus, substantia innominate, and colliculi.	Unknown.	rs63750444	Coding Exon 7	Point, Missense GGT to GAT	0	Miravalle et al., 2002; Takao et al., 2002
G217R	Alzheimer's Disease	AD : Pathogenic	Cotton wool plaques.	Increased Aβ42/Aβ40 ratio in cells and in vitro. Decreased production of Aβ40 and Aβ42 in vitro.		Coding Exon 7	Point, Missense GGT to CGT	0	Norton et al., 2009
L219F	Alzheimer's Disease	AD : Pathogenic	Unknown	Decreased Aβ40; increased Aβ42 and the Aβ42/Aβ40 ratio in vitro.	rs63749987	Coding Exon 7	Point, Missense CTT to TTT	0	Terreni et al., 2016
L219P	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in one case; meningeal CAA in cortex and cerebellum. PET and SPECT show hypoperfusion and hypometabolism in temporal lobes and right parietal lobe.	Unknown	rs63750761	Coding Exon 7	Point, Missense CTT to CCT	0	Smith et al., 1999
L219R	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but brain imaging showed atrophy and reduced blood flow in temporal, parietal, and frontal lobes. Also, widespread microbleeds were found in brain, brainstem, and cerebellum. Levels of phospho-tau in CSF were elevated, while those of Aβ42 were reduced.	Unknown.		Coding Exon 7	Point, Missense CTT to CGT	0	Ikeda et al., 2013
R220P	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed diffuse cortico-subcortical cerebral atrophy with multiple foci in the deep white matter.	Unknown; predicted probably damaging in silico.		Coding Exon 7	Point, Missense CGA to CCA	0	Piccoli et al., 2016
Q222H	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in one case.	Aβ42, but not Aβ40, detected in homogenate of proband's frontal cortex.	rs63751072	Coding Exon 7	Point, Missense CAG to CAC	0	Miklossy et al., 2003
Q222P	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown, but predicted to be probably damaging by Polyphen and deleterious by Provean. Conserved between species and PSENs; other pathogenic mutations at this site.		Coding Exon 7	Point, Missense CAG to CCG	0	Scahill et al., 2013; Ryan et al., 2016
Q222R	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ40 and Aβ42 production, as well as the Aβ42/Aβ40 ratio in vitro.	rs63750009	Coding Exon 7	Point, Missense CAG to CGG	0	Rogaeva et al., 2001
Q223R	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	Unknown, but cotton-wool plaques and neurofibrillary tangles were found in two biopsies of family members of a mutation carrier. MRI of mutation carrier revealed white matter lesions in the frontotemporal region. FDG-PET showed progressive decrease in glucose metabolism in the precuneus and posterior cingulate, with parietal regions affected later.	Decreased CSF Aβ42 in two cases. In cells, decreased Aβ40 levels (decreased Aβ43 cleavage), and increased Aβ42 levels (decreased Aβ42 cleavage). In vitro, nearly complete ablation of Aβ40 and Aβ42 production.		Coding Exon 7	Point, Missense CAG to CGG	0	Uttner et al., 2010
L226F	Alzheimer's Disease, Frontotemporal Dementia	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ40 ratio; increased Aβ42; increased Aβ40.	rs63750487	Coding Exon 7	Point, Missense CTC to TTC	0	Zekanowski et al., 2006
L226R	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in one individual, including numerous neuritic plaques and neurofibrillary tangles in the hippocampus and neocortex.	Unknown, but consistent with the helical alignment of pathogenic mutations in transmembrane domain 5.	rs63749961	Coding Exon 7	Point, Missense CTC to CGC	0	Coleman et al., 2004
I227V	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs199842082	Coding Exon 7	Point, Missense ATT to GTT	0	Koriath et al., 2018
I229F	Alzheimer's Disease	AD : Pathogenic	Unknown	In vitro, increased Aβ42 production and reduced Aβ40; increased Aβ42/Aβ40 ratio	rs63749970	Coding Exon 7	Point, Missense ATT to TTT	0	Janssen et al., 2003
S230I	Alzheimer's Disease	AD : Pathogenic	Unknown.	Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro.		Coding Exon 7	Point, Missense AGT to ATT	0	Wallon et al., 2012
S230N	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI showed diffuse atrophy, which was most severe in lateral temporal lobes and insulae.	Unknown, but predicted to be “not tolerated” by SIFT and “Probably Damaging” by PolyPhen-2.		Coding Exon 7	Point, Missense AGT to AAT	0	Ringman et al., 2017
S230R	Alzheimer's Disease	AD : Pathogenic	SPECT imaging showed bilateral parietal hypoperfusion, more marked on the left side. Postmortem evaluation revealed neuropathology consistent with AD, including advanced plaque and tangle pathology (CERAD C, Braak VI).	Unknown; predicted possibly damaging in silico.		Coding Exon 7	Point, Missense AGT to AGG	0	Sassi et al., 2014
A231P	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown; predicted damaging in silico.		Coding Exon 7	Point, Missense GCC to CCC	0	Nicolas et al., 2015
A231T	Alzheimer's Disease	AD : Pathogenic	Unknown	Decreased Aβ40 and Aβ42 production and decreased Aβ42/Aβ40 ratio in vitro.	rs63749836	Coding Exon 7	Point, Missense GCC to ACC	0	Campion et al., 1995
A231V	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown, may have a relatively mild effect because substitution is semi-conserved.	rs63750799	Coding Exon 7	Point, Missense GCC to GTC	0	Cruts et al., 1998
L232P	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI revealed diffuse cortical atrophy, especially in the frontal and parietal lobes.	Unknown, but PolyPhen-2 and SIFT predicted that this mutation is likely to be damaging.		Coding Exon 7	Point, Missense CTC to CCC	0	Park et al., 2017
M233I (G>C)	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with a diagnosis of AD, including amyloid plaques and tau-positive neurofibrillary tangles. No evidence of astrocytic gliosis, spongiosis, or prion disease.	Unknown.	rs63751479	Coding Exon 7	Point, Missense ATG to ATC	0	Portet et al., 2003
M233I (G>A)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown, but atomic structure indicates wild-type residue directly interacts with APP substrate.		Coding Exon 7	Point, Missense ATG to ATA	0	Wallon et al., 2012
M233L (A>T)	Alzheimer's Disease	FTD : Pathogenic	Unknown, but SPECT revealed hypoperfusion in posterior pariteal areas and a subsequent PET scan showed hypometabolism in prefrontal, parietal, and temporal cortices, in one case. MRI showed global cerebral atrophy.	Increased Aβ42 and decreased Aβ40 production, resulting in increased Aβ42/Aβ40 ratio in vitro. In cells, increased Aβ42/Aβ40 ratio, decreased total Aβ production and elevated levels of Aβ42 and Aβ43. Also, poromotes accumulation of APP β-CTFs which disrupt endosomes.	rs63751287	Coding Exon 7	Point, Missense ATG to TTG	0	Mendez and McMurtray, 2006
M233L (A>C)	Alzheimer's Disease	AD : Pathogenic	Unknown; imaging showed global cerebral atrophy.	In vitro, increased Aβ42 production, decreased Aβ40 production; increased Aβ42:Aβ40 ratio. In cells, increased Aβ42 and Aβ43, decreased total Aβ production, increased Aβ42:Aβ40 ratio. Disrupts endosomes via accumulation of APP β-CTF.	rs63751287	Coding Exon 7	Point, Missense ATG to CTG	0	Aldudo et al., 1999
M233T	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in at least one case.	Increased Aβ42, Aβ48, and Aβ39; Decreased Aβ40, Aβ43, and Aβ46.	rs63751024	Coding Exon 7	Point, Missense ATG to ACG	1	Kwok et al., 1997
M233V	Alzheimer's Disease	AD : Pathogenic	In one case: neurofibrillary tangles and amyloid plaques throughout the neocortex; occasional plaques in the spinal cord; Lewy bodies in the substantia nigra and cortex; moderate to severe amyloid angiopathy in leptomeningeal, cerebral, and cerebellar vessels. Widespread amyloid deposition in another patient as assessed by PET.	Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.	rs63751287	Coding Exon 7	Point, Missense ATG to GTG	0	Houlden et al., 2001
L235P	Myoclonus, Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including a high density of senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus. Tangles in the basal nucleus of Meynert, septal and raphe nuclei, and the locus coeruleus.	Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro. Expression in transgenic mice was associated with increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic protein.	rs63749835	Coding Exon 7	Point, Missense CTG to CCG	1	Campion et al., 1996
L235R	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed bilateral atrophy, especially in the temporal and parietal lobes.	Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro. Also, caused incomplete endoproteolytic processing of PSEN1. Predicted possibly damaging in silico.		Coding Exon 7	Point, Missense CTG to CGG	0	Antonell et al., 2011
L235V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in at least one case.	Decreased Aβ40 and Aβ42 production in vitro, without changing the Aβ42/Aβ40 ratio. Elevated monoamine-oxidase-A activity.	rs63751130	Coding Exon 7	Point, Missense CTG to GTG	0	Janssen et al., 2003
F237C	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown. Evolutionarily conserved codon across species and between human PSEN1 and PSEN2.		Coding Exon 7	Point, Missense TTT to TGT	0	Lanoiselée et al., 2017
F237I	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Unknown, but in proband, PET and SPECT revealed hypometabolism and hypoperfusion in bilateral temporoparietal areas, including primary and sensory motor cortices.	Decreased production of Aβ42 and Aβ40 in vitro, but Aβ42/Aβ40 ratio similar to wild-type.	rs63750858	Coding Exon 7	Point, Missense TTT to ATT	0	Sodeyama et al., 2001
F237L	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs63750858	Coding Exon 7	Point, Missense TTT to CTT	0	Janssen et al., 2003
I238_K239insI	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD (Braak and Braak stage VI, CERAD C). Cortical atrophy, mainly of the frontal lobe; Numerous neurofibrillary tangles and amyloid plaques, as well as ghost tangles, neuropil threads, and neuritic plaques; Cerebral amyloid angiopathy.	Unknown; insertion of the trinucleotide TAA results in the insertion of one amino acid (isoleucine), but does not cause a frameshift. In silico this insertion is predicted to be deleterious.		Coding Exon 7	Insertion --- to TAA	0	Roeber et al., 2015
I238M	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed progressive cerebral atrophy. PET showed hypometabolism in the frontal and temporal lobes.	Increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio when expressed in HEK293 cells expressing APP with the Swedish mutation. In vitro, abrogated production of both Aβ40 and Aβ42.		Coding Exon 7	Point, Missense ATC to ATG	0	Ting et al., 2014
K239N	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI in one case showed medial temporal lobe and frontal lobe atrophy.	In cells, Aβ42 and Aβ42/Aβ40 were increased. However, Aβ40 and Aβ42 production was undetectable in an assay using isolated proteins.		Coding Exon 7	Point, Missense AAG to AAC	0	Lladó et al., 2010
L241R	Alzheimer's Disease	AD : Pathogenic	Unknown, but mutation carrier had CSF AD biomarker levels (Aβ42, tau, phospho-tau) in the pathological range.	Unknown		Coding Exon 7	Point, Missense CTC to CGC	0	Lanoiselée et al., 2017
P242Lfs (P242LfsX11)	Familial Acne Inversa	Familial Acne Inversa : Pathogenic	Not applicable.	Decreases PSEN1 mRNA due to premature stop codon, nonsense-mediated decay. No effect on APP cleavage, but enhances Notch signaling. Also enhances cytokine and chemokine expression, and prolongs TNF-α production in monocytes and macrophages.		Coding Exon 7	Deletion CCT to CTG	0
T245P	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI showed diffuse brain atrophy in one patient, and no abnormalities in 2 others.	Undetectable production of Aβ42 and Aβ40 in in vitro assay using isolated proteins.	rs63750888	Coding Exon 7	Point, Missense ACT to CCT	0	Edwards-Lee et al., 2006
A246E	Alzheimer's Disease	AD : Pathogenic	Generalized atrophy, most prominently in the frontal lobes and hippocampus. Neuronal loss, gliosis, neurofibrillary tangles, and plaques.	Increased Aβ42 and Aβ43 secretion, Aβ42/Aβ40 ratio, Aβ42/Aβ total ratio. Decreased production of Aβ40 and Aβ42 in vitro. Disrupts endosomes via accumulation of APP β-CTF. Impaired neuronal differentiation, neural precursor proliferation, viability, autophagy, mitophagy, lysosomal function, ER calcium flux.	rs63750526	Coding Exon 7	Point, Missense GCG to GAG	4	Sherrington et al., 1995
A246P	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD (Braak and Braak stage VI, CERAD C) as well as cerebral amyloid angiopathy. Some α-synuclein inclusions were observed in the entorhinal cortex.	Unknown; predicted probably damaging in silico.		Coding Exon 7	Point, Missense GCG to CCG	0	Roeber et al., 2015
L248P	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown; predicted damaging in silico.		Coding Exon 7	Point, Missense CTC to CCC	0	Jiao et al., 2014
L248R	Alzheimer's Disease	AD : Pathogenic	Unknown; in one case, neuroimaging showed prominent atrophy in the lateral fissure, and less prominent in parietofrontal regions	Increased Aβ42/Aβ40 ratio, severely decreased production of Aβ40 and Aβ42 in vitro.		Coding Exon 7	Point, Missense CTC to CGC	0	Clarimón et al., 2008; Guerreiro et al., 2010
I249L	Amyotrophic Lateral Sclerosis, Alzheimer's Disease	ALS : Unclear Pathogenicity, AD : Pathogenic	Unknown, but MRI from one case revealed hippocampal and cortical atrophy.	Increased Aβ42 and Aβ42/Aβ40 ratio, with no effect on PSEN1 endoproteolysis or Aβ43 production, in transfected cells. In silico analyses yielded mixed results: SIFT=tolerated; PolyPhen2=possibly damaging; Mutation Taster=disease causing.	rs1363575880	Coding Exon 7	Point, Missense ATC to CTC	0	Couthouis et al., 2014
L250F	Alzheimer's Disease	AD : Pathogenic	Unknown, but CT scans showed frontal, parietal, and temporal atrophy	Unknown		Coding Exon 7	Point, Missense TTG to TTT	0	Butler et al., 2010
L250S	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in two cases.	In vitro, decreases Aβ40 and Aβ42 production; increases Aβ42/Aβ40 ratio.	rs63751163	Coding Exon 7	Point, Missense TTG to TCG	0	Hutton et al., 1996; Harvey et al., 1998
L250V	Alzheimer's Disease, Myoclonus	AD : Pathogenic, Myoclonus : Pathogenic	Unknown, but MRI sohwed diffuse cerebral atrophy and SPECT showed severe cortical hypoperfusion	Unknown	rs63750634	Coding Exon 7	Point, Missense TTG to GTG	0	Furuya et al., 2003
Y256N	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI revealed temporal lobe and hippocampal atrophy in one case.	Unknown, but in silico algorithms predict the mutation is deleterious.		Coding Exon 7	Point, Missense TAT to AAT	0	Li et al., 2019
Y256S	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in two cases; severe, widespread pathology, including cotton-wool plaques.	Increased Aβ40 and Aβ42 in frontal cortex of one case. In cells, increased Aβ42 and Aβ43. In vitro, decreased production of Aβ42 and Aβ40, increased Aβ42/Aβ40 ratio.	rs63751320	Coding Exon 7	Point, Missense TAT to TCT	0	Miklossy et al., 2003
A260G	Alzheimer's Disease	AD : Pathogenic, CAA :	Unknown, but CSF bimoarkers were consistent with AD in two patients and MRI revealed mild cortical and hippocampal atrophy in one patient and signs of CAA in two patients.	Unknown		Coding Exon 8	Point, Missense GCT to GGT	0	Ryman et al., 2014; Piaceri et al., 2020
A260V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD. Also, perivascular amyloid deposits and Pick-like intra-nueronal inclusions in the dentate gyrus.	Reduced production of Aβ40 and Aβ42; increased Aβ42/Aβ40 ratio in cells and in vitro.	rs63751420	Coding Exon 8	Point, Missense GCT to GTT	0	Rogaev et al., 1995; Ikeda et al., 1996
V261F	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic, SP : Pathogenic, CAA : Pathogenic	Neuropathology consistent with AD, with cotton-wool plaques, CAA, and degeneration of spinal lateral pyramidal tracts.	Increased Aβ43 production (prevailing Aβ species) in cells. Decreased Aβ42 and Aβ40 production, and increased Aβ42/Aβ40 ratio in vitro. Also, abolished autoproteolysis.	rs63750964	Coding Exon 8	Point, Missense GTT to TTT	0	Rogaeva et al., 2001; Farlow et al., 2000; Farlow et al., 2001
V261I	Alzheimer's Disease	AD : Pathogenic	Consistent with AD, with widespread cotton wool plaques.	Unknown.		Coding Exon 8	Point, Missense GTT to ATT	0	Miravalle et al., 2005
V261L	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	Unknown, but MRI showed cortical and subcortical atrophy, and SPECT revealed temporal hyperperfusion in one patient.	Unknown		Coding Exon 8	Point, Missense GTT to CTT	0	Jiménez Caballero et al., 2008; Gómez-Tortosa et al., 2010
L262F	Alzheimer's Disease	AD : Pathogenic	A brain biopsy from one case "confirmed the diagnosis of AD".	Increased Aβ42/Aβ40 ratio in vitro, exhibiting a moderate increase in Aβ42 production, and a decrease in Aβ40 production.	rs63750248	Coding Exon 8	Point, Missense TTG to TTC	0	Forsell et al., 1997
L262S	Alzheimer's Disease	AD : Pathogenic	Unknown	Predicted to be damaging by four different algorithms, with a PHRED-CADD score of 32.		Coding Exon 8	Point, Missense TTG to TCG	0	Wang et al., 2019
L262V	Alzheimer's Disease, Frontotemporal Dementia	AD : Pathogenic	Unknown.	Unknown; predicted probably damaging in silico.		Coding Exon 8	Point, Missense TTG to GTG	0	Wallon et al., 2012; Lohmann et al., 2012
C263F	Alzheimer's Disease	AD : Pathogenic	Unknown. AD-like CSF levels of Aβ40, Aβ42, Aβ43, tau, and phospho-tau in one carrier, but not in another.	Variable effect on CSF Aβ levels.	rs63751102	Coding Exon 8	Point, Missense TGT to TTT	0	Janssen et al., 2003
C263R	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Decreased Aβ40 and Aβ42 production and increased Aβ42/Aβ40 ratio in vitro.	rs63750543	Coding Exon 8	Point, Missense TGT to CGT	0	Wasco et al., 1995
P264L	Spastic Paraparesis, Alzheimer's Disease, Atypical Dementia, Progressive Nonfluent Aphasia	AD : Pathogenic	Variable: Neuropathology frequently consistent with a diagnosis of AD, but also significant white-matter abnormalities and severe cerebral amyloid angiopathy with numerous small cortical infarcts. Abundant cotton-wool plaques composed of Aβ42 have also been reported.	Increased Aβ42/Aβ40 and decreased Aβ38/Aβ42 ratios; increased Aβ42, and decreased Aβ40 and Aβ38 production; Deposition of PSEN-1 in the endoplasmic reticulum; impaired mitochondrial activity and ATP production.	rs63750301	Coding Exon 8	Point, Missense CCG to CTG	1	Campion et al., 1995; Wasco et al., 1995
G266S	Spastic Paraparesis, Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA : Pathogenic	In one case, cotton-wool plaques; cerebral amyloid angiopathy; temporal and frontal lobe atrophy; widespread NFTs; reactive gliosis in white matter. MRI in another case revealed parietal lobe atrophy, frontal lobe deep white matter abnormalities. SPECT showed hypoperfusion of parietal and occipital areas.	Marked increase in Aβ42/Aβ40 ratio; reduced production of Aβ42, and particularly Aβ40, in vitro.	rs121917807	Coding Exon 8	Point, Missense GGT to AGT	0	Matsubara-Tsutsui et al., 2002; Akatsu et al., 2008
P267A	Alzheimer's Disease	AD : Pathogenic	Frequent neuritic plaques, including in the neocortex (Braak stage VI); Severe cerebral amyloid angiopathy.	Unknown; predicted probably damaging in silico.		Coding Exon 8	Point, Missense CCA to GCA	0	Ringman et al., 2016
P267L	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown.	rs63750779	Coding Exon 8	Point, Missense CCA to CTA	0	Kowalska et al., 2003
P267S	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with Alzheimer's disease.	Reduced γ-secretase activity; Increased cell cycle arrest.	rs63751229	Coding Exon 8	Point, Missense CCA to TCA	0	Alzheimer's Disease Collaborative Group, 1995; Hutton et al., 1996
R269G	Alzheimer's Disease, Myoclonus	AD : Pathogenic	Unknown, but in one patient, MRI showed mild, non-specific cortical atrophy and EEG revealed a moderate, bilateral excess of slow wave activity. SPECT imaging showed non-specific, moderate hypoperfusion of the posterior parietal cortex.	Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio.	rs63751019	Coding Exon 8	Point, Missense CGT to GGT	0	Perez-Tur et al., 1996
R269H	Alzheimer's Disease, Myoclonus	AD : Pathogenic, CAA : Pathogenic	Neuropathology consistent with Alzheimer's disease; a high burden of Aβ and neurofibrillary tangles in cortical areas. Prominent microbleeds in the cerebellum, parieto-occipital region, and temporal lobe revealed by MRI in one patient. MRI in two cases showed white matter alterations.	Decreased Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ levels, and Aβ42/Aβ40 ratio in CSF of one carrier.	rs63750900	Coding Exon 8	Point, Missense CGT to CAT	0	Gómez-Isla et al., 1997
L271V	Alzheimer's Disease	AD : Pathogenic	Considerable atrophy of the temporal and posterior white matter with enlargement of the lateral ventricles. Variant plaques: large, non-cored, reminiscent of cotton-wool plaques. Depigmented locus coeruleus.	Affects splicing of exon 8 such that more transcripts are produced which lack exon 8. Causes amino acid replacement (D257A) at the splice junction of exons 7 and 9. In vitro, Aβ40 and Aβ42 production were abrogated, but in cells, increased Aβ42 secretion was reported, with no change in Aβ production.	rs63750886	Coding Exon 8	Point, Missense CTG to GTG	0	Kwok et al., 2003
V272A	Alzheimer's Disease, Parkinsonism, Subcortical Dementia	AD : Pathogenic	Neuropathology consistent with AD, but also Lewy bodies in cortex and substantia nigra, and widespread subcortical neuritic lesions. MRI and PET abnormalities in subcortical-frontal areas in later stages of disease.	Increased plasma Aβ42. In vitro, increased Aβ42 production and Aβ42/Aβ40.	rs63750680	Coding Exon 8	Point, Missense GTT to GCT	0	Jimenez-Escrig et al., 2004
V272D	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI in one case revealed frontotemporal atrophy.	Increased Aβ42/Aβ40 ratio in cultured cells.		Coding Exon 8	Point, Missense GTT to GAT	0	Mengel et al., 2020
E273A	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42 and Aβ42/Aβ40 ratio in vitro; disrupted calcium flow in ER.	rs63750772	Coding Exon 8	Point, Missense GAA to GCA	0	Kamimura et al., 1998
E273G	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown.		Coding Exon 8	Point, Missense GAA to GGA	0	Wallon et al., 2012
T274R	Alzheimer's Disease	AD : Pathogenic	Unknown	In vitro, Aβ40 and Aβ42 production was undetectable.	rs63750284	Coding Exon 8	Point, Missense ACA to AGA	0	Rogaeva et al., 2001
A275V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Moderately decreased Aβ40 production and increased Aβ42/Aβ40 ratio in vitro.		Coding Exon 8	Point, Missense GCT to GTT	0	Luedecke et al., 2014
R278I	Alzheimer's Disease, Progressive Nonfluent Aphasia	AD : Pathogenic, Progressive Nonfluent Aphasia : Pathogenic	Unknown; MRI showed multiple white-matter foci in 2 carriers; atrophy was minimal or absent in 3 carriers, and cortical amyloid deposition seen in one carrier.	Deficient maturation of mutant protein in iPSC-derived neurons. Selective increase in secreted Aβ43; impaired endoproteolysis of PSEN1. Increased Aβ42/Aβ40, Aβ42/Aβ38, and particularly Aβ43/Aβ40 ratios. Aβ38/Aβ40 ratio similar to wild-type. Impaired processing of the ApoER2 LDL receptor.	rs63749891	Coding Exon 8	Point, Missense AGA to ATA	1	Godbolt et al., 2004
R278K	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic, SP : Pathogenic	Unknown; MRI and CT scans reported as normal in one individual	Increased Aβ42 production in patient fibroblasts; but reduced Aβ42 and Aβ40 production in assay with purified proteins. In both cases, increased Aβ42/Aβ40.	rs63749891	Coding Exon 8	Point, Missense AGA to AAA	0	Assini et al., 2003
R278S	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs63750524	Coding Exon 8	Point, Missense AGA to AGC	0	Raman et al., 2007
R278T	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD was detected in one brain biopsy.	Unknown	rs63749891	Coding Exon 8	Point, Missense AGA to ACA	0	Kwok et al., 1997
E280A (Paisa)	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including severe brain atrophy, Aβ pathology, and hyperphosphorylated tau tangles. Aβ42 may be particularly abundant in the cerebral cortex, hippocampus, cerebellum, midbrain, and basal ganglia. Frequent CAA and cerebellar damage including ubiquitin–positive plaques, reactive astrocytes, and dystrophic neurites.	In cortex, increased Aβ42 and decreased Aβ38 and Aβ43 compared with sporadic AD. In cells, increased Aβ42/Aβ40 ratio; increased Aβ42 compared with wildtype PSEN1, and isolated proteins produce less Aβ40 and Aβ42. In cells, stress vulnerability with increased tau phosphorylation, and impairment of sodium channels, calcium homeostasis, mitochondrial function, AChE activity, and autophagy.	rs63750231	Coding Exon 8	Point, Missense GAA to GCA	0	Alzheimer's Disease Collaborative Group, 1995; Lopera et al., 1997; Lemere et al., 1996
E280G	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Frequent cotton-wool plaques and vascular amyloid deposits; Some cases with white-matter abnormalities and degeneration of the corticospinal tract.	Increased Aβ42/Aβ40 ratio in cells and in vitro. Aβ42 secretion was increased in cells, but production of both Aβ42 and Aβ40 was reduced in vitro, as was endoproteolytic processing of PSEN1.	rs63750231	Coding Exon 8	Point, Missense GAA to GGA	0	Alzheimer's Disease Collaborative Group, 1995; O'Riordan et al., 2002
E280K	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed generalized brain atrophy, including atrophy of the hippocampus.	Unknown; predicted probably damaging in silico.		Coding Exon 8	Point, Missense GAA to AAA	0	Ch'ng et al., 2015
L282F	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed mild medial temporal atrophy. FDG-PET showed glucose hypometabolism in the bilateral parietal cortices and posterior cingulate gyri.	Unknown.		Coding Exon 8	Point, Missense CTT to TTT	0	Hamaguchi et al., 2009
L282P	Alzheimer's Disease	AD : Pathogenic	Unknown, but in one patient, MRI revealed mild, diffuse cortical atrophy, and FDG-PET showed severe, bilateral hypometabolism in parietal and temporal cortices.	Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerated (SIFT). CADD score = 28.5		Coding Exon 8	Point, Missense CTT to CCT	0	Kim et al., 2020
L282R	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with Alzheimer's disease.	Decreased Aβ42 and obliterated Aβ40 production in vitro.	rs63750050	Coding Exon 8	Point, Missense CTT to CGT	0	Aldudo et al., 1998
L282V	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic	Extensive neurofibrillary tangles and amyloid deposits including both dense-cored plaques and diffuse plaques. Severe cerebral amyloid angiopathy (CAA) in the neocortex, hippocampus, and cerebellum. CAA deposits associated with dystrophic neurites and inflammatory gliosis. Severe white-matter loss. Cerebellar amyloid pathology associated with severe CAA and loss of Purkinje cells.	A twofold increase in the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1. In vitro, Aβ42 and Aβ40 production, as well as Aβ42/Aβ40 ratio, similar to wild-type. Impairs trafficking of the APOE receptor apoER2.	rs63749937	Coding Exon 8	Point, Missense CTT to GTT	0	Dermaut et al., 2001
F283L	Alzheimer's Disease, Corticobasal Syndrome	AD : Pathogenic	Neuropathology consistent with AD; absence of CBD pathology (2 cases in 1 family). MRI showed severe parietal, perirolandic, and temporal atrophy with relative sparing of frontal and ipsilateral hippocampal regions.	Unknown, but predicted to have a damaging effect according to SIFT, Polyphen, and Mutation Taster.		Coding Exon 8	Point, Missense TTT to TTG	0	Scahill et al., 2013; Ryan et al., 2016
P284L	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	Prominent cotton-wool plaques in the cerebral cortex, basal ganglia, brainstem, and spinal cord. Some dense core plaques, primarily in the hippocampus and cerebral cortex. Vacuolar changes. Amyloid angiopathy. Neurofibrillary tangles. Mild neuritic changes and gliosis.	Unknown.	rs63750863	Coding Exon 8	Point, Missense CCA to CTA	0	Tabira et al., 2002
P284S	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	Unknown, but MRI revealed widespread white-matter lesions in 4 family members, and lobar microbleeds in two members.	Aβ40 and Aβ42 production was similar to wild-type PSEN1 in vitro.	rs63750324	Coding Exon 8	Point, Missense CCA to TCA	0	Marrosu et al., 2006
A285S	Alzheimer's Disease	AD : Pathogenic	Unknown, but in one case, PiB-PET was positive, MRI revealed bilateral hippocampal atrophy, and FDG-PET showed bilateral hypometabolism in the temporal cortex.	Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and tolerable (SIFT). CADD score = 25.9.		Coding Exon 8	Point, Missense GCT to TCT	0	Kim et al., 2020
A285V	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI from 2 patients showed atrophy of the temporo-parietal cortex and hippocampus, and abnormalities in the deep white matter of the pariteo-occipital lobes. SPECT revealed hypoperfusion in parietal and occipital areas.	Aβ40 and Aβ42 levels similar to controls in CSF of one patient. In cells, Aβ42 production elevated compared to Aβ40 and Aβ38 production. In vitro, both Aβ40 and Aβ42 production modestly reduced; Aβ42/Aβ40 similar to wild-type PSEN1.	rs63751139	Coding Exon 8	Point, Missense GCT to GTT	0	Ikeda et al., 1996
L286P	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA : Pathogenic	Cotton wool plaques and severe amyloid angiopathy (2 cases); brain hematoma at early age (3 cases).	Decreased Aβ37, Aβ38, Aβ39, and Aβ42 in patient CSF; increased Aβ15 and Aβ20. Increased Aβ42/43 amyloid production in cultured cells; reduced production rates of Aβ38 and Aβ40 in isolated brain membranes, and decreased Aβ38/Aβ42 ratio.		Coding Exon 8	Point, Missense CTC to CCC	0	Sánchez-Valle et al., 2007
L286V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ total ratio in cells. In vitro, decreased Aβ40 and Aβ42 production. Disrupts intracellular calcium dynamics.	rs63751235	Coding Exon 8	Point, Missense CTC to GTC	11	Sherrington et al., 1995
T291A	Alzheimer's Disease	AD : Unclear Pathogenicity, Parkinsonism : Unclear Pathogenicity	Unknown, patient with 2 PSEN1 mutations (A434T, T291A) had AD pathology with cotton wool plaques, diffuse deposits, and severe amyloid angiopathy	Unknown, but in silico analyses predicted it to be possibly damaging (PoyPhen) and neutral (Provean).		Coding Exon 9	Point, Missense ACA to GCA	0	Ryan et al., 2016
T291P	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding.	In cells, this mutation increased both Aβ40 and Aβ42, causing an overall increase in the Aβ42/Aβ40 ratio. However, in an in vitro assay, it dramatically decreased Aβ42 and abolished Aβ40 production. Also affects exon 9 splicing.	rs63750298	Coding Exon 9	Point, Missense ACA to CCA	0	Dumanchin et al., 2006
W294Ter	Acute Encephalopathy, Retinitis Pigmentosa	Retinitis Pigmentosa : Pathogenic	Unknown, but MRI of two carriers showed white matter and subcortical lesions, and a third carrier had lesions in the occipital and parietal cortices. All 3 carriers had abnormal EEG recordings.	Unknown, but 3D in silico modeling predicted pronounced structural effects.		Coding Exon 9	Point, Nonsense TGG to TAG	0	You et al., 2020
P303L	Frontotemporal Dementia	FTD : Unclear Pathogenicity	Unknown.	Unknown.	rs147638016	Coding Exon 9	Point, Missense CCG to CTG	0	Koriath et al., 2018
K311R	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42 and reduced Aβ40 levels in conditioned media of cultured cells, resulting in increased Aβ42:Aβ40. Also increased phosphorylated tau levels in cell lysates.	rs115865530	Coding Exon 9	Point, Missense AAA to AGA	0	Dong et al., 2017
E318G	None	AD : Unclear Pathogenicity	Mixed results. Some carriers have AD neuropatholgy, but some do not.	Mixed results. Some carriers have increased CSF tau and phospho-tau; increased plasma Aβ40. In vitro, reduced production of Aβ40 and Aβ42, but increased secretion of both peptides in cells.	rs17125721	Coding Exon 9	Point, Missense GAA to GGA	0	Sandbrink et al., 1996; Cruts et al., 1998; Aldudo et al., 1998
D333G	Dilated Cardiomyopathy	AD : Unclear Pathogenicity	Unknown	Aβ42 production slightly reduced in vitro. Altered calcium signaling in fibroblasts.	rs121917809	Coding Exon 10	Point, Missense GAT to GGT	0	Li et al., 2006
R352C	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; imaging showed cerebral global atrophy.	Slight decrease of Aβ42 and Aβ40 production, with Aβ42/Aβ40 ratio similar to wildtype as assessed in vitro.		Coding Exon 10	Point, Missense CGC to TGC	0	Jiang et al., 2015
R352_S353insR	Frontotemporal Dementia	FTD : Unclear Pathogenicity	Unknown, single case with confirmed mutation had FTD symptoms and pathology, but was subsequently found to also have a progranulin mutation	In-frame insertion of 3 nucleotides in exon 10 resulting in insertion of an arginine between amino acids R352 and S353. Aβ CSF and plasma levels in proband are roughly normal. In cultured cells, expression of the mutant increased the Aβ42:Aβ40 ratio, but markedly reduced the levels of both secreted Aβ40 and Aβ42. In vitro, production of Aβ42 was markedly decreased and production of Aβ40 was abolished.	rs63750762	Coding Exon 10	Insertion CGC.TCT to CGC.CGC.TCT	0	Rogaeva et al., 2001; Tang-Wai et al., 2002; Amtul et al., 2002
T354I	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but brain imaging showed generalized atrophy in one case and cortical parieto-temporal hypometabolism in another. CSF levels of Aβ42, total tau, and phospho-tau were consistent with AD in the latter case.	Decreased Aβ42 and Aβ40 production, and decreased Aβ42/Aβ40 ratio in vitro. Decreased Aβ42 in CSF of one case.	rs63751164	Coding Exon 10	Point, Missense ACA to ATA	0	Rogaeva et al., 2001; Lee et al., 2006
P355S	Alzheimer's Disease, Frontotemporal Dementia	AD : Unclear Pathogenicity	Unkonwn, but MRI revealed microbleeds in cortex, basal ganglia, and subcortical white matter suggestive of amyloid angiopathy. FDG-PET showed bilateral frontotemporal hypometabolism. Lewy body pathology suspected.	Unknown, but cryo-EM data suggest perturbation of γ-secretase catalytic activity.	rs376433615	Coding Exon 10	Point, Missense CCT to TCT	0	Monacelli et al., 2019
R358Q	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Decreased Aβ40 and Aβ42 production and increased Aβ42/Aβ40 ratio in vitro. in cells, increased Aβ40 and Aβ42 secretion, with no significant change in the Aβ42/Aβ40 ratio.	rs63751174	Coding Exon 10	Point, Missense CGA to CAA	0	Rogaeva et al., 2001
A360T	Alzheimer's Disease	AD : Pathogenic	Unknown. In mutation carrier, CSF Aβ42 was reduced, but tau and phospho-tau levels were normal	Unknown	rs199715992	Coding Exon 10	Point, Missense GCT to ACT	0	Lanoiselée et al., 2017
S365A	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	In vitro production of Aβ38, Aβ40, Aβ42, and Aβ43 similar to wildtype in one study; in another Aβ40 and Aβ42 production moderately increased, with Aβ42/Aβ40 ratio unchanged. Another study reported the phosphorylation status of this site appears to modulate a PSEN1 calcium-triggered conformational change linked to increased Aβ42/Aβ40.		Coding Exon10	Point, Missense TCC to GCC	0	Clarimón et al., 2008; Guerreiro et al., 2010
S365Y	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.	rs63750941	Coding Exon 10	Point, Missense TCC to TAC	0	Rogaeva et al., 2001
G371C	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Unknown		Coding Exon 10	Point, Missense GGT to TGT	0	Perrone et al., 2020
R377M	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs63751051	Coding Exon 11	Point, Missense AGG to ATG	0	Janssen et al., 2003
R377W	Alzheimer's Disease	AD : Pathogenic	Unknown; in one case, imaging showed amyloid deposition in the precuneus and frontal and parietal areas, with mild parietal atrophy and hypometabolism in precuneus, posterior cingulum, inferior parietal lobes, temporal, and frontal lobes. Frontotemporal atrophy and hypometabolism seen in another case.	In vitro, decreased Aβ42 production and abrogated Aβ40 production.		Coding Exon 10	Point, Missense AGG to TGG	0	Wallon et al., 2012; Borroni et al., 2011
G378E	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA : Pathogenic	Neuropathology consistent with AD. One case also had notable cerebral amyloid angiopathy.	Increased Aβ42/Aβ40 ratio; increased Aβ42.	rs63750323	Coding Exon 11	Point, Missense GGA to GAA	0	Besançon et al., 1998
G378R		AD : Pathogenic	Unknown, but MRI of one patient showed fronto-temporo-parietal atrophy and CSF biomarkers consistent with AD.	Unknown, but predicted deleterious in silico and two other pathogenic mutations in same residue.		Coding Exon 11	Point, Missense GGA to CGA	0	Ramos-Campoy et al., 2020
G378V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Decreased Aβ42 and abrogation of Aβ40 production in vitro. Predicted to have a damaging effect by SIFT, Polyphen, and Mutation Taster.	rs63750323	Coding Exon 11	Point, Missense GGA to GTA	0	Janssen et al., 2003
G378fs	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; MRI showed hippocampal and parahippocampal atrophy.	The insertion of one nucleotide in exon 11 is predicted to cause a frameshift. In cells, Aβ40 and Aβ42 production decreased and Aβ42/Aβ40 ratio increased.		Coding Exon 11	Insertion GGA.GTA to GGG.AGT	0	El Kadmiri et al., 2014
L381F	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including neuritic amyoid plaques and neurofibrillary tangles. Hirano bodies and granulovacuolar degeneration in the hippocampus.	In silico analysis suggests that the mutation affects the folding free energy and flexibility of the protein.		Coding Exon 11	Point, Missense CTT to TTT	0	Dolzhanskaya et al., 2014
L381V	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42/Aβ40 ratio; increased Aβ42; Reduced presenilin-1 N-terminal fragment (NTF), suggesting impaired endoproteolysis of presenilin-1.	rs63750687	Coding Exon 11	Point, Missense CTT to GTT	0	Dintchov Traykov et al., 2009; Mehrabian et al., 2004
G384A	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ40 ratio; increased Aβ42 and Aβ42+; decreased Aβ40, Aβ38, Aβ38/Aβ42, and Aβ40/Aβ43. Abolishes PSEN1's activity as an ER calcium leak channel.	rs63750646	Coding Exon 11	Point, Missense GGA to GCA	0	Cruts et al., 1995; Tanahashi et al., 1996
F386I	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed atrophy of hippocampus.	Unknown; predicted damaging in silico.		Coding Exon 11	Point, Missense TTC to ATC	0	Shea et al., 2017
F386L	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown, but predicted to be pathogenic by in silico analyses (SIFT and PolyPhen2).	rs1555358095	Coding Exon 11	Point, Missense TTC to TCA	0	Yagi et al., 2014
F386S	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42/Aβ40 ratio in cells and in vitro. In vitro assays indicated reduced production of both Aβ40 and Aβ42; cell-based assays showed increased secretion of both peptides.	rs63749860	Coding Exon 11	Point, Missense TTC to TCC	0	Raux et al., 2005
F388L	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42 and Aβ42/Aβ40 ratio.		Coding Exon 11	Point, Missense TTC to TTG	0	Zhan et al., 2017
Y389H	Parkinsonism, Alzheimer's Disease	AD : Pathogenic	Unknown, but in two cases, amyloid-PET was positive. MRI revealed mild, diffuse cortical atrophy in one case, and severe frontotemporal atrophy in another. FDG-PET showed bilateral hypometabolism in parietal and temporal cortices in one case.	Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerable/damaging (SIFT). CADD score = 26.9.		Coding Exon 11	Point, Missense TAC to CAC	0	Park et al., 2020; Kim et al., 2020
Y389S	Alzheimer's Disease	AD : Pathogenic	Unknown, but one case had Aβ accumulation (PiB-PET+), with mild, diffuse cortical atrophy (MRI), and bilateral hypometabolism in the parieto-temporal cortex (FDG-PET).	Unknown, but predicted probably damaging by in silico algorithms Polyphen2 and SIFT. CADD score = 26.8.		Coding Exon 11	Point, Missense TAC to TCC	0	Kim et al., 2020
S390I	Alzheimer's Disease	AD : Pathogenic	Unknown	Drastic decrease in production of both Aβ40 and Aβ42 in vitro.	rs63750883	Coding Exon 11	Point, Missense AGT to ATT	0	Campion et al., 1999
S390N	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed cerebral amyloid angiopathy.	Unknown.		Coding Exon 11	Point, Missense AGT to AAT	0	Nicolas et al., 2015
V391F	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42/Aβ40 ratio; reduced Aβ40 production in vitro.	rs63751066	Coding Exon 11	Point, Missense GTT to TTT	0	Raux et al., 2005
V391G	Alzheimer's Disease	AD : Pathogenic, Parkinsonism :	Unknown; in single case MRI showed generalized mild cortical and subcortical atrophy, thinner hippocampus, and enlarged ventricles.	Unknown, probable damaging as predicted by SIFT, Poly-Phen-2, and Mutation Taster. Phenotype complicated by family history of extrapyramidal disease with several associated recessive mutations (PANK2, SYNE1, ZNF592)		Coding Exon 11	Point, Missense GTT to GGT	0	Lou et al., 2017
L392P	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown	rs63750218	Coding Exon 11	Point, Missense CTG to CCG	0	Tedde et al., 2000
L392V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD, including cortical atrophy, amyloid plaques, and neurofibrillary tangles.	Increased Aβ42:Aβ40 ratio; increased Aβ48-39 production line, including Aβ42, in cells; decreased Aβ40 production in vitro. Impaired Notch cleavage.	rs63751416	Coding Exon 11	Point, Missense CTG to GTG	0	Campion et al., 1995; Campion et al., 1995; Rogaev et al., 1995; Campion et al., 1999
V393F	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown, but predicted deleterious by in silico analysis (CADD Phred score= 35).		Coding Exon 11	Point, Missense GTT to TTT	0	Koriath et al., 2018
G394V	Alzheimer's Disease	AD : Pathogenic	Unknown	In vitro, Aβ40 production undetectable; Aβ42 drastically reduced; autoproteolysis abrogated. Four algorithms predicted the mutation to be damaging, with a PHRED-CADD score of 31. In patient cells with additional mutation (E318G), no change in Aβ40 or Aβ42 levels.	rs63750929	Coding Exon 11	Point, Missense GGT to GTT	0	Rogaeva et al., 2001
A396T	Alzheimer's Disease	AD : Pathogenic	Neuropathology was consistent with AD, plus widespread α-synuclein inclusions characteristic of Lewy body disease, in one case. MRI of another case showed atrophy of the frontal lobes.	Increased Aβ40 and Aβ42 production with Aβ42/Aβ40 ratio unchanged in cells; reduced Aβ40 production and increased Aβ42/Aβ40 ratio in vitro.		Coding Exon 11	Point, Missense GCC to ACC	0	Lohmann et al., 2012
N405S	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Decreased Aβ40 and Aβ42 production, and decreased Aβ42/Aβ40 ratio in vitro.	rs63751254	Coding Exon 11	Point, Missense AAC to AGC	0	Yasuda et al., 2000
I408T	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI of the proband showed marked enlargement of the lateral ventricles and hippocampal atrophy typical of AD.	Unknown; predicted damaging in silico.		Coding Exon 11	Point, Missense ATA to ACA	0	Tedde et al., 2016
A409T	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Decreased Aβ40 and Aβ42 production and decreased Aβ42/Aβ40 ratio in vitro.	rs63750227	Coding Exon 11	Point, Missense GCC to ACC	0	Aldudo et al., 1999
C410Y	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Increased Aβ42/Aβ total ratio; decreased production of Aβ42, Aβ40, NTF, CTF, AICD. Conflicting data on Aβ43 production. Dominant-negative inhibition of Aβ peptide production by wild-type PSEN1. Partial loss of γ-secretase mediated cleavage of Notch and β-neurexin.	rs661	Coding Exon 11	Point, Missense TGT to TAT	0	Sherrington et al., 1995; Campion et al., 1995
V412I	Frontotemporal Dementia	FTD : Unclear Pathogenicity	Unknown; in one case, 18FDG-PET showed hypometabolism in the parietal and frontal cortices, as well as in the putamen and caudate. In another case, SPECT showed widespread cortical hypoperfusion.	Severe decrease in Aβ42 and undetectable Aβ40 levels in in vitro assay using isolated proteins.		Coding Exon 11	Point, Missense GTA to ATA	0	Bernardi et al., 2009
I416T	Alzheimer's Disease	AD : Pathogenic	Unknown, but two cognitively normal mutation carriers had preclinical amyloid plaques and tau accumulation, as assessed by PET, similar to those of individuals at-risk for late-onset AD or individuals carrying other AD-causing PSEN1 mutations.	Unknown, but mutation results in the substitution of a highly conserved, transmembrane, hydrophobic amino acid with a polar amino acid near a splice site. Computational algorithms (SIFT, PolyPhen2 HDIV and HVAR, MutationTaster, FATHMM, MetaSVM, PROVEAN, and REVEL) predict deleteriousness.		Coding Exon 12	Point, Missense ATT to ACT	0	Ramirez Aguilar et al., 2019
G417A	Alzheimer's Disease, Parkinsonism	AD : Pathogenic	Unknown, but MRI and PET are consistent with AD in one case. PiB-PET showed diffuse amyloid in the cerebellum, and the frontal, parietal, and temporal cortices.	Unknown, but in silico analyses predict mutation is damaging (PolyPhen2, SIFT, Provean). Changes in amino acid bulkiness, polarity, and hydrophobicity, together with 3D modeling, suggest reduced flexibility in transmembrane helix. Splicing may also be affected.		Coding Exon 12	Point, Missense GGT to GCT	0	Giau et al., 2018
G417S	Alzheimer's Disease	AD : Pathogenic, SP : Pathogenic	Cotton wool plaques throughout cortex, abundant Aβ deposits in cerebellum and spinal gray matter (one patient). Also, CAA, extensive neuronal loss, astrocytic and microglial markers, and extensive distribution of neocortical Lewy bodies. TDP-43 inclusions in limbic region and temporal cortex.	Unknown		Coding Exon 12	Point, Missense GGT to AGT	0	Miki et al., 2019
L418F	Alzheimer's Disease	AD : Pathogenic	Unknown	Decreased Aβ40 and Aβ42 production, and elevated Aβ42/Aβ40 ratio, in vitro.	rs63751316	Coding Exon 11	Point, Missense TTG to TTT	0	Rogaeva et al., 2001
L420R	Alzheimer's Disease	AD : Pathogenic	Extensive amyloid pathology, primarily in the form of cotton-wool plaques, although some rare dense core plaques. Some amyloid angiopathy.	Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.	rs63750802	Coding Exon 12	Point, Missense CTT to CGT	0	Shrimpton et al., 2007
L424F	Alzheimer's Disease	AD : Pathogenic	Unknown, but neuroimaging in two patients revealed brain atrophy with white-matter changes.	Unknown		Coding Exon 12	Point, Missense CTC to TTC	0	Mehrabian et al., 2006
L424H	Alzheimer's Disease, Atypical Dementia	AD : Pathogenic	Unknown; generalized cerebral atrophy by MRI; diffuse cerebral hypoperfusion by SPECT.		rs63751032	Coding Exon 12	Point, Missense CTC to CAC	0	Raux et al., 2005; Zekanowski et al., 2006
L424P	Alzheimer's Disease	AD : Pathogenic	Unknown, but in proband, MRI showed medial temporal lobe atrophy and global cortical atrophy; PET showed hypometabolism in parietal areas, the precuneus, and the posterior cingulate cortex. Also, reduced CSF Aβ42.	Unknown, but predicted pathogenic by in silico algorithms (MutationTaster, PolyPhen, Provean, and SIFT). 3D in silico analysis predicted shortening of two intramembrane α-helices and creation of a new one.		Coding Exon 12	Point, Missense CTC to CCC	0	Guven et al., 2019
L424R	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	Unknown; MRI showed cortical and subcortical atrophy with a thin corpus callosum.	Unknown, MRI showed cortical and subcortical atrophy with a thin corpus callosum.	rs63751032	Coding Exon 12	Point, Missense CTC to CGC	0	Kowalska et al., 1999
L424V	Atypical Dementia	AD : Pathogenic, Atypical Dementia : Pathogenic	Unknown; CT and SPECT imaging showed diffuse cortical and subcortical atrophy and hypoperfusion affecting the frontal, temporal, and parietal lobes in one patient. In another, fronto-temporal atrophy was predominant, as revelaed by CT and MRI.	Increased Aβ40, Aβ42, and Aβ42/Aβ40 in vitro.		Coding Exon 12	Point, Missense CTC to GTC	0	Robles et al., 2009
A426P	Alzheimer's Disease	AD : Pathogenic	Unknown, but PiB-PET revealed robust amyloid deposition in the striatum. PiB retention was also found in the neocortex and thalamus. Compared to sporadic AD, amyloid accumulation in frontal, temporoparietal, and precuneus cortices was lower.	Slight decrease in Aβ40 and Aβ42 production in vitro; Aβ42/Aβ40 ratio similar to controls. In silico analyses predicted the mutation to be tolerated (SIFT) and probably damaging (Polyphen2).	rs63751223	Coding Exon 12	Point, Missense GCC to CCC	0	Poorkaj et al., 1998
A431E (Jalisco)	Alzheimer's Disease	AD : Pathogenic, SP : Pathogenic	Neuropathology consistent with AD. Widespread white-matter abnormalities in several patients with motor impairments. In one case, Lewy body pathology.	Reduced Aβ37, Aβ38, Aβ39, Aβ40, and Aβ42 levels, as well as Aβ42/Aβ40 ratio, in CSF. Increased Aβ42 in plasma. In vitro, reduced production of Aβ40 and Aβ42. Enhances MAO-A activity in cells.	rs63750083	Coding Exon 12	Point, Missense GCA to GAA	0	Rogaeva et al., 2001; Yescas et al., 2006
A431V	Alzheimer's Disease	AD : Pathogenic	Unknown, but in one case FDG-PET at MCI-AD stage showed low metabolic rates in posterior cingulate gyrus, posterior and lateral parietal cortices, and medial temporal regions; elevated tau and phospho-tau in CSF.	Unknown. At MCI-AD stage, normal CSF Aβ42 levels	rs63750083	Both Exon 12	Point, Missense GCA to GTA	0	Matsushita et al., 2002
P433S	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42, Aβ43, and Aβ42/Aβ40 ratio in transfected cells. Reduced PSEN1 endoproteolysis.		Coding Exon 12	Point, Missense CCA to TCA	0	Koriath et al., 2018
A434C	Alzheimer's Disease	AD : Pathogenic	Numerous diffuse plaques and neuritic plaques with dense amyloid cores throughout the neocortex; Abundant neurofibrillary tangles and Hirano bodies; Moderate cell loss and gliosis in the hippocampus, amygdala, and nucleus basalis.	Increased Aβ42 and decreased Aβ40 production in vitro, resulting in an increased Aβ42/Aβ40 ratio.	rs63750528, rs63750341	Coding Exon 12	Point, Double GCT to TGT	0	Devi et al., 2000
A434T	Parkinsonism, Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown; predicted damaging in silico.		Coding Exon 12	Point, Missense GCT to ACT	0	Jiao et al., 2014
L435F	Alzheimer's Disease	AD : Pathogenic	Widespread cotton-wool plaques in the neocortex, hippocampus, and deep cerebral nuclei contain substantially more Aβ43 than typical plaques. Abundant neurofibrillary tangles in the entorhinal cortex and hippocampus. Mild cerebral amyloid angiopathy. Neuronal loss, depigmentation, and gliosis in the substantia nigra.	Decreased Aβ42, Aβ40, APP-CTF, Notch-1 ICD. Elevated Aβ43 in cells, inluding iPSC-derived neurons, knockin rats, and human brain tissue, but decreased Aβ43 in knockin mice. Impairs wildtype PSEN1 γ-secretase activity.	rs63750001	Coding Exon 12	Point, Missense CTT to TTT	1	Rogaeva et al., 2001
P436Q	Alzheimer's Disease, Spastic Paraparesis	AD : Pathogenic	Neuropathology consistent with AD in at least one mutation carrier, including frequent Aβ plaques, many of the cotton-wool type, and severe neurofibrillary tangle pathology (Braak and Braak stage VI).	Unknown.	rs121917808	Coding Exon 12	Point, Missense CCA to CAA	0	Taddei et al., 1998
P436S	Alzheimer's Disease	AD : Pathogenic	Unknown	Increased Aβ42/Aβ40 ratio in cells and in vitro. In cells, decreased production of Aβ40, Aβ42, AICD, Notch. In vitro, decreased Aβ40, with no effect on Aβ42 production.	rs63749925	Coding Exon 12	Point, Missense CCA to TCA	0	Palmer et al., 1999
I437V	Alzheimer's Disease	AD : Pathogenic	Unknown.	Decreased Aβ40 and Aβ42 production, and increased Aβ42/Aβ40 ratio in vitro.		Coding Exon 12	Point, Missense ATC to GTC	0	Nicolas et al., 2015
I439S	Alzheimer's Disease	AD : Pathogenic	Unknown, but MRI showed diffuse cortical atrophy in one case.	Unknown, but PolyPhen analysis predicted the mutation is possibly damaging.		Coding Exon 12	Point, Missense ATC to AGC	0	Gómez-Tortosa et al., 2010
I439V	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	In vitro, moderately increased Aβ40 and Aβ42 production; Aβ42/Aβ40 ratio unchanged. In cells, increased Aβ42 secretion; Aβ42/Aβ40 unchanged.	rs63750249	Coding Exon 12	Point, Missense ATC to GTC	0	Rogaeva et al., 2001
T440del	Alzheimer's Disease, Dementia with Lewy Bodies	PDD : Pathogenic, AD : Pathogenic	Cotton-wool plaques, Lewy bodies, CAA, neuronal loss in cortex and substantia nigra, corticospinal tract degeneration in one case.	Abrogation of Aβ40 production and dramatic reduction of Aβ42 production in vitro. Near abrogation of autoproteolysis.	rs63750470	Coding Exon 12	Deletion ACC to ---	0	Ishikawa et al., 2005
S290C;T291_S319del (ΔE9Finn, Δ9Finn, Δ9)	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Variable across two families: One family had unusual plaques described as “reminiscent of loosely packed cotton-wool balls” which were large (100-150 μM in diameter) and not congophilic, suggesting a lack of amyloid at the core, in addition to more typical AD plaques and tangles. The other family had more typical AD pathology.	4.6 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.		Both Intron 8, Exon 9	Complex	0	Crook et al., 1998; Prihar et al., 1999
S290C;T291_S319del (ΔE9, Δ9)	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Variable: lesions observed include cotton-wool plaques, cored plaques, and tangles. Corticospinal tract degeneration, cortical atrophy, and congophilic amyloid angiopathy also variably observed.	5.9 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.		Both Intron 8, Exon 9	Complex	0	Smith et al., 2001
S290C;T291_S319del A>G (ΔE9, Δ9, c.869-2A>G)	Alzheimer's Disease	AD : Pathogenic	Unknown; in one patient, MRI showed supratentorial atrophy, particularly of parietal and occipital cortex. Also, reduced Aβ42 in CSF.	Point mutation in splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.		Both Intron 8, Exon 9	Complex	0	Rovelet-Lecrux et al., 2015
S290C;T291_S319del G>A (ΔE9, Δ9, c.869-1G>A)	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Cotton-wool plaques are common, in addition to classic neuritic, amyloid plaques. Tangles, neuronal loss, atrophy typical of AD.	Point mutation in splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.	rs63750219	Both Intron 8, Exon 9	Complex	0	Sato et al., 1998
S290C;T291_S319del G>T (ΔE9, Δ9)	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Cotton-wool plaques throughout the neocortex. Less frequent cored plaques. Neurofibrillary tangles, some neuronal loss, gliosis, and cerebral amyloid angiopathy.	Point mutation in a splice acceptor site in intron 8 resulting in in-frame skipping of exon 9 and S290C change at the splice junction of exon 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.	rs63750219	Both Intron 8, Exon 9	Complex	0	Perez-Tur et al., 1995; Hutton et al., 1996
S290W;S291_R377del (Δ9-10 , Delta9-10, p.Ser290_Arg377delinsTrp, g.73671948_73682054del)	Alzheimer's Disease, Spastic Paraparesis	Early-onset : Pathogenic	No data.	This mutation involves the deletion of 10.1 kilobases including exons 9 and 10. A S290W missense mutation is predicted at the junction between exons 8 and 11.		Both Introns 8-10, Exons 9-10	Deletion	0	Le Guennec et al., 2017; Lanoiselée et al., 2017
c.869-22_869-23ins18 (ΔE9, Δ9, deltaE9)	Spastic Paraparesis, Alzheimer's Disease	AD : Pathogenic	Cotton-wool plaques in addition to widespread neurofibrillary tangles and neuritic plaques more typical of AD. Marked cerebral amyloid angiopathy.	Insertion of 18 nucleotides in intron 8 upstream of exon 9, resulting in exon 9 skipping. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.		Both Intron 8, Exon 9	Insertion	0	Dumanchin et al., 2006
c.*947G>A		AD : Unclear Pathogenicity	Unknown, associated with increased thickness in the inferior frontal and orbitofrontal cortices, and basal ganglia	Unknown	rs7523	Non-Coding 3' UTR	Point	0	Seo et al., 2020

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PSEN1 (322)