Mutations
PSEN-2
The gene PSEN2 encodes presenilin-2, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. Missense mutations in PSEN2 are a rare cause of early onset Alzheimer's disease.

Search Results
PSEN2 (64)
Mutation | Clinical Phenotype |
Pathogenicity | Neuropathology | Biological Effect | Genomic Position | Genomic Region | Mutation Type Codon Change |
Research Models |
Primary Papers |
---|---|---|---|---|---|---|---|---|---|
T18M |
Parkinson's Disease | PD : Unclear Pathogenicity | Unknown. | Unknown; predicted pathogenic in silico. | rs143061887 |
Coding Exon 3 |
Point, Missense ACG to ATG |
0 | Blauwendraat et al., 2016 |
R29H |
None | AD : Not Pathogenic | Not applicable. | Unknown. | Coding Exon 3 |
Point CGC to CAC |
0 | Guerreiro et al., 2010 | |
G34S |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unchanged Aβ42/Aβ40 ratio. | Coding Exon 3 |
Point GGC to AGC |
0 | Sleegers et al., 2004 | |
R62C |
Alzheimer's Disease, None | AD : Unclear Pathogenicity | Unknown. | Reduced levels of CSF Aβ43 and Aβ42, and increased Aβ40; decreased Aβ42/Aβ40 ratio in one carrier. | rs150400387 |
Coding Exon 4 |
Point CGC to TGC |
0 | Sleegers et al., 2004; Ertekin-Taner et al., 2008; Brouwers et al., 2008 |
R62H |
Alzheimer's Disease, Frontotemporal Dementia, Parkinson's Disease Dementia | AD : Not Pathogenic, FTD : Not Pathogenic | Unknown. In two carriers, CSF biomarker levels were variable. | In two carriers, CSF Aβ peptide levels were variable. In cells, unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. | rs58973334 |
Coding Exon 4 |
Point, Missense CGC to CAC |
0 | Cruts et al., 1998; Gallo et al., 2010 |
P69A |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unknown. | Coding Exon 4 |
Point, Missense CCC to GCC |
0 | Dobricic et al., 2012 | |
R71W |
Alzheimer's Disease, None, Parkinson's Disease Dementia | AD : Not Pathogenic | Leukoencephalopathy with periventricular white-matter lacunar infarctions. | Unchanged Aβ42/Aβ40 ratio; Reduces the stability of the presenilin-2 protein and impairs Notch signaling. | rs140501902 |
Coding Exon 4 |
Point, Missense CGG to TGG |
0 | Sleegers et al., 2004 |
K82fs |
Frontotemporal Dementia | Tauopathy consistent with Pick's Disease : Unclear Pathogenicity | Neuropathology consistent with Pick's disease. | Frameshift starting at K82; reduced mutant protein in frontal cortex and hippocampus. | Coding Exon 4 |
Deletion AAA to A-- |
0 | Perrone et al., 2018 | |
K82R |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; neuroimaging showed diffuse cortical atrophy, especially in the posterior region and mild hippocampal atrophy. FDG-PET showed widespread hypometabolism. PIB-PET showed amyloid deposition in the frontal lobe, lateral temporal lobe, parietal lobe, posterior cingulate cortex, precuneus, and striatum.
|
Unknown. | Coding Exon 4 |
Point, Missense AAA to AGA |
0 | Shi et al., 2015 | |
A85V |
Alzheimer's Disease, Dementia with Lewy Bodies | AD : Pathogenic, DLB : Unclear Pathogenicity | Amyloid deposition; Neurofibrillary changes; Diffuse Lewy bodies in the neocortex; Bilateral basal ganglia calcifications. | Unknown. | rs63750048 |
Coding Exon 4 |
Point, Missense GCG to GTG |
0 | Piscopo et al., 2008 |
V101M |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unknown; predicted probably damaging in silico. | Coding Exon 4 |
Point, Missense GTG to ATG |
0 | Sala Frigerio et al., 2015 | |
K115Efs* |
Alzheimer's Disease | AD : Pathogenic | Neuropathology was consistent with AD. | The deletion of two nucleotides from exon 5 leads to a frameshift and ultimately to a premature stop codon in exon 6. In patient fibroblasts, secretion of Aβ40 was decreased, and Aβ38 and Aβ42 were undetectable. Wild-type PSEN2 levels were also decreased. Alternatively spliced transcripts of the mutant allele were detected in brain. | Coding Exon 4 |
Deletion AAG to A-- |
0 | Jayadev et al., 2010 | |
T122P |
Alzheimer's Disease | AD : Pathogenic | Unknown. | Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. | rs63749851 |
Coding Exon 5 |
Point, Missense ACG to CCG |
0 | Finckh et al., 2000 |
T122R |
Atypical Dementia | Atypical Dementia : Pathogenic | Variable cortical and subcortical atrophy. | Reduced calcium ion released from intracellular stores. | rs28936380 |
Coding Exon 5 |
Point, Missense ACG to AGG |
0 | Binetti et al., 2003 |
P123L |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions. | Unknown; predicted probably damaging in silico. | Coding Exon 5 |
Point, Missense CCA to CTA |
0 | Xia et al., 2015 | |
E126fs |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; neuroimaging showed hippocampal and parahippocampal atrophy. | Unknown; the insertion of one nucleotide (A) is predicted to result in a frameshift at codon 126. | Coding Exon 5 |
Insertion GAG.GAC to GAA.GGA |
0 | El Kadmiri et al., 2014 | |
E126K |
Alzheimer's Disease | AD : Pathogenic | Unknown. | Unknown; predicted probably damaging in silico. | Coding Exon 5 |
Point, Missense GAG to AAG |
0 | Müller et al., 2014 | |
S130L |
Alzheimer's Disease, None, Parkinson's Disease Dementia | AD : Unclear Pathogenicity | Neuropathology consistent with AD at autopsy in at least one case. Reduced CSF Aβ43/Aβ40 and Aβ42/Aβ40 ratios in another case, with slightly elevated tau and normal phospho-tau CSF levels. | Decreased Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ, as well as Aβ42/Aβ40 and Aβ43/Aβ40 ratios in CSF of one carrier. However, in transfected cells, unchanged Aβ42/Aβ40 ratio, Aβ42, PSEN2-CTF, and PSEN2-NTF. | rs63750197 |
Coding Exon 5 |
Point, Missense TCG to TTG |
0 | Sorbi et al., 2002; Tedde et al., 2003 |
V139M |
Alzheimer's Disease, None | AD : Unclear Pathogenicity | Bilateral hypoperfusion in the parietal-temporal lobes. | Unknown. | Coding Exon 5 |
Point, Missense GTG to ATG |
0 | Bernardi et al., 2008 | |
N141D |
Alzheimer's Disease | AD : Pathogenic | Unknown | Unknown, but 3 algorithms predict damaging with a PHRED CADD score of 24.9. | Coding Exon 5 |
Point, Missense AAC to GAC |
0 | Wang et al., 2019 | |
N141I (Volga German) |
Alzheimer's Disease | AD : Pathogenic | Extensive amyloid plaques; Extensive neurofibrillary tangles (typically a Braak score of V or VI); α-synuclein inclusions, especially in the amygdala; Rare TDP-43 pathology; Hippocampal sclerosis. | Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. Altered microglial phenotype. | rs63750215 |
Coding Exon 5 |
Point, Missense AAC to ATC |
5 | Levy-Lahad et al., 1995; Rogaev et al., 1995 |
N141Y |
Alzheimer's Disease | AD : Pathogenic | Proband had autopsy-confirmed AD with severe brain atrophy and numerous plaques and neurofibrillary tangles. | Unknown; predicted damaging in silico. | rs61761208 |
Coding Exon 5 |
Point, Missense AAC to TAC |
0 | Niu et al., 2014 |
L143H |
None | AD : Not Pathogenic | Not applicable. | Unknown. | Coding Exon 5 |
Point, Missense CTC to CAC |
0 | Guerreiro et al., 2010 | |
V148I |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. | rs63750812 |
Coding Exon 5 |
Point, Missense GTC to ATC |
0 | Lao et al., 1998 |
I149T |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Unknown | Coding Exon 5 |
Point, Missense ATC to ACC |
0 | Perrone et al., 2020 | |
V150M |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Unknown, but predicted damaging in silico. | rs866044092 |
Coding Exon 5 |
Point, Missense GTG to ATG |
0 | Gao et al., 2019 |
T153S |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Decreased Aβ42 and Aβ43 in CSF of one carrier. Also reduced Aβ40, sAPPα, and sAPPβ. | Coding Exon 5 |
Point, Missense ACC to AGC |
0 | Perrone et al., 2020 | |
K161R |
Alzheimer's Disease | AD : Pathogenic | Unknown. | Unknown. | Coding Exon 5 |
Point, Missense AAG to AGG |
0 | Wallon et al., 2012 | |
R163C |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Unknown, but predicted damaging by in silico algorithms. | rs200931244 |
Coding Exon 5 |
Point, Missense CGC to TGC |
0 | Gao et al., 2019 |
R163H |
None | AD : Not Pathogenic | Not applicable. | Unknown. | rs778936527 |
Coding Exon 5 |
Point, Missense CGC to CAC |
0 | Puschmann et al., 2009 |
H169N |
Alzheimer's Disease, Frontotemporal Dementia, Progressive Nonfluent Aphasia | AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown; neuroimaging showed mild atrophy and widespread hypometabolism. PIB-PET showed amyloid deposition in the AD case, but no amyloid deposition in the FTD case. | Unknown. | Coding Exon 6 |
Point, Missense CAT to AAT |
0 | Shi et al., 2015 | |
M174V |
Alzheimer's Disease, Frontotemporal Dementia | AD : Not Pathogenic | Unknown; imaging has shown frontal atrophy and hypoperfusion in temporoparietal regions. | Unknown; predicted benign in silico. | rs61757781 |
Coding Exon 6 |
Point, Missense ATG to GTG |
0 | Andreoli et al., 2008; Clarimón et al., 2008; Guerreiro et al., 2010 |
S175C |
Alzheimer's Disease | AD : Pathogenic | Unknown; MRI showed focal atrophy in the medial temporal lobe; SPECT showed bilateral hypoperfusion in temporoparietal regions. | Unknown. | Coding Exon 6 |
Point, Missense TCT to TGT |
0 | Piscopo et al., 2010 | |
G212V |
Alzheimer's Disease | AD : Pathogenic | Neuropathology consistent with AD. | Unknown; predicted pathogenic in silico. | Coding Exon 7 |
Point, Missense GGG to GTG |
0 | Marín-Muñoz et al., 2016 | |
V214L |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; neuroimaging showed diffuse cortical atrophy and widespread hypometabolism. | Unknown; structural changes were predicted in silico, especially at amino acids 214, 219, and 220. PolyPhen2 predicted a probably or possibly damaging effect. | Coding Exon 7 |
Point, Missense GTG to TTG |
0 | Youn et al., 2014 | |
Q228L |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unknown. | rs63750880 |
Coding Exon 7 |
Point, Missense CAG to CTG |
0 | Zekanowski et al., 2003 |
Y231C |
Frontotemporal Dementia | FTD : Pathogenic | Unknown; MRI showed diffuse subcortical and cortical atrophy, particularly in the frontotemporoparietal lobes. | Unknown. | Coding Exon 7 |
Point, Missense TAC to TGC |
0 | Marcon et al., 2009 | |
I235F |
Alzheimer's Disease, None | AD : Unclear Pathogenicity | Unknown. | Increased Aβ42/Aβ40 ratio in cells. | Coding Exon 7 |
Point, Missense ATC to TTC |
0 | Lee et al., 2014 | |
S236S |
AD : Unclear Pathogenicity | Unknown, but in one patient PET showed amyloid deposition and MRI revealed atrophy in temporo-insular cortices. FDG-PET showed diffuse hypometabolism in the cortex and striatum. | Unknown. | rs61730652 |
Coding Exon 7 |
Point, Silent AGT to AGC |
0 | Coppola et al., 2020 | |
A237V |
Alzheimer's Disease | AD : Unclear Pathogenicity | Neuropathology consistent with AD. | Unknown; predicted possibly damaging in silico. | rs200670135 |
Coding Exon 7 |
Point, Missense GCG to GTG |
0 | Sassi et al., 2014 |
L238F |
Alzheimer's Disease | AD : Pathogenic | Unknown. | Increased Aβ42/Aβ40 ratio in cellular assay. | Coding Exon 7 |
Point, Missense CTC to TTC |
0 | Sala Frigerio et al., 2015 | |
L238P |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; MRI showed supratentorial cortical atrophy, particularly atrophy of the parietal cortex. | Unknown; predicted damaging in silico. | Coding Exon 8 |
Point, Missense CTC to CCC |
0 | Blauwendraat et al., 2016 | |
M239I |
Alzheimer's Disease | AD : Pathogenic | Moderate cortical atrophy; Numerous neurofibrillary tangles; Numerous senile plaques, especially in the amygdala. | Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF; Reduced calcium release. | rs63749884 |
Coding Exon 7 |
Point, Missense ATG to ATA |
0 | Finckh et al., 2000 |
M239V |
Alzheimer's Disease | AD : Pathogenic | Diffuse cerebral atrophy; Senile plaques; Neurofibrillary tangles (stage VI of Braak and Braak); Ectopic neurons in the subcortical white matter; Extracellular "ghost" neurofibrillary tangles. | Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. | rs28936379 |
Coding Exon 7 |
Point, Missense ATG to GTG |
0 | Rogaev et al., 1995 |
A252T |
None | AD : Not Pathogenic | Not applicable. | Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio. | rs138836272 |
Coding Exon 7 |
Point, Missense GCG to ACG |
0 | Guerreiro et al., 2010 |
A258T |
None | AD : Not Pathogenic | Not applicable. | Unknown. | rs148238688 |
Coding Exon 7 |
Point, Missense GCC to ACC |
0 | Sala Frigerio et al., 2015 |
A258V |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Predicted not pathogenic in silico. | rs14443227784 |
Coding Exon 7 |
Point, Missense GCC to GTC |
0 | Yagi et al., 2014 |
R284G |
AD : Pathogenic | Unknown. | Increased Aβ42 and Aβ42/Aβ40 in a cell assay. | rs1208742830 |
Coding Exon 8 |
Point, Missense AGA to GGA |
0 | Hsu et al., 2018 | |
P287P |
AD : Unclear Pathogenicity | Unknown, but associated with increased glucose metabolism in the bilateral fronto-temporo-parietal cortices. | Unknown. | rs75733498 |
Coding Exon 8 |
Point, Silent CCC to CCT |
0 | Seo et al., 2020 | |
T301M |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unchanged Aβ42/Aβ40 ratio. | rs144277432 |
Coding Exon 7 |
Point, Missense ACG to ATG |
0 | Croes et al., 2004 |
K306fs |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; neuroimaging showed cortical atrophy. | Unknown; the deletion of a single nucleotide (A) in exon 9 is predicted to result in a frameshift at codon 306. | Coding Exon 9 |
Deletion AAG.CTG to AGC.TGG |
0 | El Kadmiri et al., 2014 | |
P334A |
Alzheimer's Disease, None | AD : Not Pathogenic | Not applicable. | Unknown. | Coding Exon 10 |
Point, Missense CCT to GCT |
0 | Lee et al., 2014 | |
P334R |
Alzheimer's Disease, None | AD : Not Pathogenic | Not applicable. | Unknown. | rs63750207 |
Coding Exon 10 |
Point, Missense CCT to CGT |
0 | Lleó et al., 2002 |
P348L |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Decreased Aβ40; increased Aβ42/Aβ40 ratio in cell assay. | Coding Exon 10 |
Point, Missense CCA to CTA |
0 | Blauwendraat et al., 2016 | |
A377V |
Alzheimer's Disease, None | AD : Not Pathogenic | Not applicable. | Unknown. | Coding Exon 11 |
Point, Missense GCG to GTG |
0 | Lee et al., 2014 | |
A379D |
Alzheimer's Disease | AD : Pathogenic | Unknown | Unknown, but predicted damaging in silico. PHREDD CADD score = 27.1 | Coding Exon 11 |
Point, Missense GCC to GAC |
0 | Wang et al., 2019 | |
V393M |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; bilateral hypometabolism in the parieto-occipital regions. | Unchanged Aβ42/Aβ40 ratio in cells. In one assay, reduced secretion of Aβ4 and Aβ42, in another, Aβ42 secretion was unchanged. | rs142690225 |
Coding Exon 11 |
Point, Missense GTG to ATG |
0 | Lindquist et al., 2008 |
T421M |
Alzheimer's Disease | AD : Pathogenic | Unknown | Predicted to be pathogenic in silico (SIFT, PolyPhen2, Pmut). | rs756609078 |
Coding Exon 12 |
Point, Missense ACG to ATG |
0 | Yagi et al., 2014 |
T430M |
Alzheimer's Disease | AD : Unclear Pathogenicity | Right frontotemporal hypoperfusion. | Unknown. | rs63750666 |
Coding Exon 12 |
Point, Missense ACG to ATG |
0 | Ezquerra et al., 2003 |
P436L |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown, but MRI of one carrier showed bilateral atrophy of the temporal lobe and hippocampus. | Unknown. | Coding Exon 12 |
Point, Missense CCG to CTG |
0 | Han et al., 2020 | |
D439A |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown; imaging showed moderate cortical atrophy in the frontal and parietal regions. | MIxed results in vitro. | rs63750110 |
Coding Exon 12 |
Point, Missense GAC to GCC |
0 | Lleó et al., 2001 |
G359fs (Intron 11/12 delA) |
Mild Cognitive Impairment, Alzheimer's Disease | AD : Unclear Pathogenicity, MCI : Unclear Pathogenicity | Unknown, but MRI of MCI patient revealed mild atrophy in the hippocampus, and SPECT showed decreased metabolism in posterior and temporal cortices. | Deletion of an adenine in intron 11/12 resulting in exon 12 skipping and a frameshift starting at codon G359; new termination codon in the 3' UTR. Reduced PSEN2 levels due to instability. CADD-PHRED = 23.9. | Both Intron 11/12 |
Deletion |
0 | Perrone et al., 2018 | |
G359fs (Intron 11/12 delAG) |
Amyotrophic Lateral Sclerosis | ALS : Unclear Pathogenicity | Unknown. | Deletion of an adenine in intron 11/12 resulting in exon 12 skipping and a frameshift starting at codon G359; new termination codon in the 3' UTR. | Both Intron 11/12 |
Deletion |
0 | Perrone et al., 2018 | |
Intron 9/12 C>T |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Unknown. PHRED CADD score of 9.977. | rs1230394996 |
Non-Coding Intron 9/12 |
Point |
0 | Wang et al., 2019 |