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.

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Search Results

PSEN2 (80)

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 4
Point, Missense
ACG to ATG
0 Blauwendraat et al., 2016
A23A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown, but 3 of 4 carriers (also carrying PSEN2 N43N) had atrophy consistent with AD as assessed by MRI. Unknown

rs11405
Coding
Exon 4
Point, Silent
GCT to GCC
0 Eryilmaz et al., 2021
R29H
None AD : Benign Not applicable. Unknown.

Coding
Exon 4
Point
CGC to CAC
0 Guerreiro et al., 2010
G34S
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unchanged Aβ42/Aβ40 ratio.

Coding
Exon 4
Point
GGC to AGC
0 Sleegers et al., 2004
N43N
Alzheimer's Disease AD : Unclear Pathogenicity Unknown, but 3 of 4 carriers (also carrying PSEN2 A23A) had atrophy consistent with AD as assessed by MRI. Unknown.

rs6759
Coding
Exon 4
Point, Silent
AAC to AAT
0 Eryilmaz et al., 2021
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 5
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 : Benign, FTD : Benign 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 5
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 5
Point, Missense
CCC to GCC
0 Dobricic et al., 2012
R71W
Alzheimer's Disease, None, Parkinson's Disease Dementia AD : Benign 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 5
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 5
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 5
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 5
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 5
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 5
Deletion
AAG to A--
0 Jayadev et al., 2010
G117Ter
Alzheimer's Disease AD : Not Classified Unknown Unknown, but in silico prediction of deleteriousness was high (CADD = 40).

Coding
Exon 5
Point, Nonsense
GGA to TGA
0 Mao et al., 2021
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 6
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 6
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 6
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 6
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 6
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 6
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 6
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 6
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 6
Point, Missense
AAC to ATC
5 Levy-Lahad et al., 1995;
Rogaev et al., 1995
N141S
Alzheimer's Disease AD : Not Classified Unknown. Unknown, but in silico algorithms predicted damaging (CADD > 20).

Coding
Exon 6
Point, Missense
AAC to AGC
0 Mao et al., 2021
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 6
Point, Missense
AAC to TAC
0 Niu et al., 2014
L143H
None AD : Benign Not applicable. Unknown.

Coding
Exon 6
Point, Missense
CTC to CAC
0 Guerreiro et al., 2010
I146T
Alzheimer's Disease AD : Not Classified Unknown Unknown, but predicted damaging in silico (CADD > 20).

rs1215971988
Coding
Exon 6

ATC to ACC
0 Mao et al., 2021
S147N
Alzheimer's Disease AD : Not Classified Unknown Unknown, but in silico analyses predicted damaging (CADD>20).

Coding
Exon 6
Point, Missense
AGC to AAC
0 Mao et al., 2021
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 6
Point, Missense
GTC to ATC
0 Lao et al., 1998
I149T
Alzheimer's Disease AD : Unclear Pathogenicity Unknown Unknown

Coding
Exon 6
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 6
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 6
Point, Missense
ACC to AGC
0 Perrone et al., 2020
K161R
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 6
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 6
Point, Missense
CGC to TGC
0 Gao et al., 2019
R163H
None AD : Benign Not applicable. Unknown.

rs778936527
Coding
Exon 6
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 7
Point, Missense
CAT to AAT
0 Shi et al., 2015
M174I
Alzheimer's Disease AD : Not Classified Neuropathology consistent with AD.  Unknown, but in silico algorithm predicted damaging (PHRED-scaled CADD > 20).

Coding
Exon 7
Point, Missense
ATG to ATA
0 Wong et al., 2019
M174V
Alzheimer's Disease, Frontotemporal Dementia AD : Benign Unknown; imaging has shown frontal atrophy and hypoperfusion in temporoparietal regions. Unknown; predicted benign in silico.

rs61757781
Coding
Exon 7
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.

rs775145486
Coding
Exon 7
Point, Missense
TCT to TGT
0 Piscopo et al., 2010
S175F
Alzheimer's Disease AD : Pathogenic Unknown, but in one case brain imaging showed atrophy and hypometabolism consistent with AD. Unknown, but multiple in silico algorithms suggest it is damaging.

Coding
Exon 7
Point, Missense
TCT to TTT
0 Guven et al., 2021
F183S
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown

Coding
Exon 7
Point, Missense
TTC to TCC
0 Wojtas et al., 2012
G212V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unknown; predicted pathogenic in silico.

Coding
Exon 8
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 8
Point, Missense
GTG to TTG
0 Youn et al., 2014
H220Y
Alzheimer's Disease AD : Not Classified Unknown Unknown, but in silico algorithms predict damaging (CADD > 20).

Coding
Exon 8
Point, Missense
CAC to TAC
0 Mao et al., 2021
Q228L
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs63750880
Coding
Exon 8
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 8
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 8
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 8
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 8
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 8
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 8
Point, Missense
ATG to ATA
0 Finckh et al., 2000
M239T
Alzheimer's Disease AD : Unclear Pathogenicity Unknown, but florbetapir-PET indicated amyloid accumulation in one carrier and CSF biomarkers were consistent with AD in another. Atrophy of the parietal lobe was observed in both patients, with one of them also having occipital cortex atrophy. In the latter patient, FDG-PET suggested hypometabolism in parietal, temporal, and occipital cortices.  Unknown, but in silico algorithms predicted deleterious (PHRED-scaled CADD score > 20).

Coding
Exon 8
Point, Missense
ATG to ACG
0 Li et al., 2021;
Jiao et al., 2021;
Mao et al., 2021
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 8
Point, Missense
ATG to GTG
0 Rogaev et al., 1995
A252T
None AD : Benign Not applicable. Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio.

rs138836272
Coding
Exon 8
Point, Missense
GCG to ACG
0 Guerreiro et al., 2010
A258T
None AD : Benign Not applicable. Unknown.

rs148238688
Coding
Exon 8
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 8
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 9
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 9
Point, Silent
CCC to CCT
0 Seo et al., 2020
M298T
Alzheimer's Disease AD : Uncertain Significance Unknown. Unknown. Some, but not all, in silico algorithms predicted damaging (PHRED-scaled CADD>20).

rs1482790603
Coding
Exon 10
Point, Missense
ATG to ACG
0 Wang et al., 2019
T301M
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unchanged Aβ42/Aβ40 ratio.

rs144277432
Coding
Exon 10
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 10
Deletion
AAG.CTG to AGC.TGG
0 El Kadmiri et al., 2014
P334A
Alzheimer's Disease, None AD : Benign Not applicable. Unknown.

Coding
Exon 11
Point, Missense
CCT to GCT
0 Lee et al., 2014
P334R
Alzheimer's Disease, None AD : Benign Not applicable. Unknown.

rs63750207
Coding
Exon 11
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 11
Point, Missense
CCA to CTA
0 Blauwendraat et al., 2016
I368F
Alzheimer's Disease AD : Not Classified Unknown Unknown, but multiple in silico algorithms predicted a damaging effect (PHRED-scaled CADD >20).

Coding
Exon 12
Point, Missense
ATC to TTC
0 Mao et al., 2021
F369S
Alzheimer's Disease AD : Not Classified Unknown, but MRI in one case showed progressive brain atrophy, particularly in the temporal lobe and hippocampus.  Unknown, but in silico algorithms predict damaging effect (CADD > 20)

Coding
Exon 12
Point, Missense
TTC to TCC
0 Wan et al., 2021
A377V
Alzheimer's Disease, None AD : Benign Not applicable. Unknown.

Coding
Exon 12
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 12
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 12
Point, Missense
GTG to ATG
0 Lindquist et al., 2008
A394Pfs*8
Alzheimer's Disease AD : Not Classified Unknown Unknown

Coding
Exon 12
Deletion
GCC to CCA
0 Jiao et al., 2021
A415S
Alzheimer's Disease AD : Not Classified Unknown, but MRI revealed global cerebral and cerebellar atrophy. CSF biomarkers were consistent with AD. Unknown, but in silico algorithm predicted damaging (PHRED-scaled CADD > 20).

Coding
Exon 13
Point, Missense
GCC to TCC
0 Wong et al., 2019
T421M
Alzheimer's Disease AD : Pathogenic Unknown Predicted to be pathogenic in silico (SIFT, PolyPhen2, Pmut).

rs756609078
Coding
Exon 13
Point, Missense
ACG to ATG
0 Yagi et al., 2014
T430M
Alzheimer's Disease AD : Unclear Pathogenicity Right frontotemporal hypoperfusion. Unknown.

rs63750666
Coding
Exon 13
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 13
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 13
Point, Missense
GAC to GCC
0 Lleó et al., 2001
G359Lfs*74 (Intron 11 delA)
Alzheimer's Disease, Mild Cognitive Impairment 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 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
Point
0 Perrone et al., 2018
G359Lfs*74 (Intron 11 delAG)
Amyotrophic Lateral Sclerosis ALS : Unclear Pathogenicity Unknown. Deletion of an adenine in intron 11 resulting in exon 12 skipping and a frameshift starting at codon G359; new termination codon in the 3' UTR.

Both
Intron 11
Deletion
0 Perrone et al., 2018
c.887-3C>T
(rs1230394996)
Alzheimer's Disease AD : Unclear Pathogenicity Unknown Unknown. PHRED CADD score of 9.977.

rs1230394996
Non-Coding
Intron 9
Point
0 Wang et al., 2019