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Search Results

PSEN2 (90)

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.

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
T18M
Alzheimer's Disease, MSA-P AD : Benign, PD : Not Classified

Unknown.

Unknown; predicted pathogenic in silico (CADD>20).



rs143061887
Exon 4 Point, Missense
ACG to ATG
0 Blauwendraat et al., 2016
A23A
Alzheimer's Disease AD : Benign

Unknown.

Unknown, but in silico algorithm predicted non-deleterious (CADD = 5.75).



rs11405
Exon 4 Point, Silent
GCT to GCC
0 Eryilmaz et al., 2021
R29H
Alzheimer's Disease AD : Uncertain Significance

Not applicable.

Unknown.



Exon 4 Point
CGC to CAC
0 Guerreiro et al., 2010
G34S
Alzheimer's Disease AD : Benign

Unknown, but in one case, brain MRI showed multiple ischemic foci of the bilateral frontal-parietal lobe and brain atrophy.

Unchanged Aβ42/Aβ40 ratio.



Exon 4 Point
GGC to AGC
0 Sleegers et al., 2004
N43N
Alzheimer's Disease AD : Benign

Unknown.

Unknown.



rs6759
Exon 4 Point, Silent
AAC to AAT
0 Eryilmaz et al., 2021
R62C
Alzheimer's Disease, None AD : Benign

Unknown. 

Reduced levels of CSF Aβ43 and Aβ42, and increased Aβ40; decreased Aβ42/Aβ40 ratio in one carrier.



rs150400387
Exon 5 Point
CGC to TGC
0 Sleegers et al., 2004
R62H
Alzheimer's Disease, Frontotemporal Dementia, Parkinson's Disease Dementia AD : Benign, FTD : Not Classified

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
Exon 5 Point, Missense
CGC to CAC
0 Cruts et al., 1998;
Gallo et al., 2010
C65Y
svPPA svPPA : Not Classified

Unknown. In one case, CSF biomarkers (Aβ42, tau, and phospho-tau) were inconsistent with AD.

Unknown. In silico predictions were mixed (PHRED-scaled CADD = 19.4).



rs766446160
Exon 5 Point, Missense
TGT to TAT
0 Ramos-Campoy et al., 2020
P69A
Alzheimer's Disease AD : Benign

Unknown.

Unknown, but scored low for deleteriousness in silico (PHRED-scaled CADD <20).



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
Exon 5 Point, Missense
CGG to TGG
0 Sleegers et al., 2004
L79P
Alzheimer's Disease AD : Not Classified

Unknown, but CSF biomarkers consistent with AD.

Unknown, but some in silico algorithms predicted damaging (PHRED-scaled CADD>20).



rs760961297
Exon 5 Point, Missense
CTG to CCG
0 Ramos-Campoy et al., 2020
K82R
Alzheimer's Disease AD : Not Classified

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.

 

Aβ42/Aβ40 ratio, and Aβ42 and Aβ40 secretion similar to control in cellular assay.



Exon 5 Point, Missense
AAA to AGA
0 Shi et al., 2015
K82fs
Frontotemporal Dementia Tauopathy consistent with Pick's Disease : Not Classified

Neuropathology consistent with Pick's disease.

Frameshift starting at K82; reduced mutant protein in frontal cortex and hippocampus.



Exon 5 Deletion
AAA to A--
0 Perrone et al., 2018
A85V
Alzheimer's Disease, Dementia with Lewy Bodies AD : Benign, DLB : Not Classified

In one carrier: amyloid deposition; neurofibrillary changes; diffuse Lewy bodies in the neocortex. 

No detectable effect on Aβ40 and Aβ42 secretion, nor the Aβ42/Aβ40 ratio in transfected cells.



rs63750048
Exon 5 Point, Missense
GCG to GTG
0 Piscopo et al., 2008
I100I
Late-onset AD : Likely Benign

Unknown.

Unknown, but predicted benign in silico (PHRED-scaled CADD score = 6.52).



rs200801915
Exon 5
ATC to ATT
0 Wang et al., 2023
V101M
Alzheimer's Disease AD : Not Classified

Unknown.

Unknown; predicted probably damaging in silico.



Exon 5 Point, Missense
GTG to ATG
0 Sala Frigerio et al., 2015
K115Efs*
(K115Efx10)
Alzheimer's Disease AD : Uncertain Significance

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.



Exon 5 Deletion
AAG to A--
0 Jayadev et al., 2010
G117Ter
(G117X)
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but in silico prediction of deleteriousness was high (CADD = 40).



Exon 5 Point, Nonsense
GGA to TGA
0 Mao et al., 2021
T122P
Alzheimer's Disease AD : Likely Pathogenic

Unknown.

Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.



rs63749851
Exon 6 Point, Missense
ACG to CCG
0 Finckh et al., 2000
T122R
Atypical Dementia Atypical Dementia : Not Classified

Variable cortical and subcortical atrophy.

Reduced calcium ion released from intracellular stores.



rs28936380
Exon 6 Point, Missense
ACG to AGG
0 Binetti et al., 2003
P123L
Alzheimer's Disease AD : Not Classified

Unknown; Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions.

Increased Aβ42 and decreased Aβ40 secretion in cells, resulting in an approximately 2-fold increase in the Aβ42/Aβ40 ratio.



Exon 6 Point, Missense
CCA to CTA
0 Xia et al., 2015
E126K
Alzheimer's Disease AD : Not Classified

Unknown.

Unknown; predicted probably damaging in silico (PHRED-scaled CADD >20).



Exon 6 Point, Missense
GAG to AAG
0 Müller et al., 2014
E126fs
Alzheimer's Disease AD : Not Classified

Unknown; neuroimaging showed hippocampal and parahippocampal atrophy.

Reduced Aβ42 and Aβ40 secretion, as well as the Aβ42/Aβ40 ratio in a cellular assay.



Exon 6 Insertion
GAG.GAC to GAA.GGA
0 El Kadmiri et al., 2014
S130L
Alzheimer's Disease, None, Parkinson's Disease Dementia AD : Uncertain Significance

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.

In transfected cells, unchanged Aβ42/Aβ40 ratio, Aβ42, PSEN2-CTF, and PSEN2-NTF. Altered calcium signaling in cells.

 

 



rs63750197
Exon 6 Point, Missense
TCG to TTG
0 Sorbi et al., 2002;
Tedde et al., 2003
L135R
Frontotemporal Dementia FTD : Not Classified

Unknown

Unknown, but PHRED-scaled CADD score was above 20 suggesting a damaging effect.



rs1272015481
Exon 6 Point, Missense
CTC to CGC
0 Koriath et al., 2018
V139M
Alzheimer's Disease, None AD : Benign

Bilateral hypoperfusion in the parietal-temporal lobes.

In transfected cells, Aβ42 and Aβ40 levels, as well as Aβ42/Aβ40 ratio, were not significantly different from control.



Exon 6 Point, Missense
GTG to ATG
0 Bernardi et al., 2008
N141Y
Alzheimer's Disease AD : Likely Pathogenic

Proband had autopsy-confirmed AD with severe brain atrophy and numerous plaques and neurofibrillary tangles.

Unknown; predicted damaging in silico.



rs61761208
Exon 6 Point, Missense
AAC to TAC
0 Niu et al., 2014
N141D
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but 3 algorithms predict damaging with a PHRED CADD score of 24.9. 



Exon 6 Point, Missense
AAC to GAC
0 Wang et al., 2019
N141I
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 PSEN2-CTF and PSEN2-NTF. Altered microglial phenotype. In 3-D brain organoids, elevated Aβ42/Aβ40 ratio, asynchronous calcium transients, and neuronal hyperactivity. Cytokine overproduction in mice. Exon 6 skipping in ~10% of mutated transcripts, reduced mRNA stability.

 



rs63750215
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).



Exon 6 Point, Missense
AAC to AGC
0 Mao et al., 2021
L143H
None AD : Not Classified

Not applicable.

Unknown, but in silico analysis predicts a deleterious effect (PHRED-scaled CADD > 20).



Exon 6 Point, Missense
CTC to CAC
0 Guerreiro et al., 2010
I146T
Alzheimer's Disease AD : Uncertain Significance

Unknown

Unknown, but predicted damaging in silico (CADD > 20).



rs1215971988
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).



Exon 6 Point, Missense
AGC to AAC
0 Mao et al., 2021
V148I
Alzheimer's Disease AD : Benign

Unknown.

Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.



rs63750812
Exon 6 Point, Missense
GTC to ATC
0 Lao et al., 1998
I149T
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but in silico analysis predicts a damaging effect (PHRED-scaled CADD >20).



Exon 6 Point, Missense
ATC to ACC
0 Perrone et al., 2020
V150M
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but predicted damaging in silico (PHRED-scaled CADD score >20).



rs866044092
Exon 6 Point, Missense
GTG to ATG
0 Gao et al., 2019
T153S
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but in silico analysis suggests damaging effect (PHRED-scaled CADD score =25.9).

 



Exon 6 Point, Missense
ACC to AGC
0 Perrone et al., 2020
K161R
Alzheimer's Disease AD : Not Classified

Unknown.

Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score = 32).



Exon 6 Point, Missense
AAG to AGG
0 Wallon et al., 2012
R163C
Alzheimer's Disease AD : Uncertain Significance

Unknown

Unknown, but predicted damaging by in silico algorithms.



rs200931244
Exon 6 Point, Missense
CGC to TGC
0 Gao et al., 2019
R163H
None AD : Benign

Not applicable.

Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score > 20).



rs778936527
Exon 6 Point, Missense
CGC to CAC
0 Puschmann et al., 2009
H169N
Alzheimer's Disease, Frontotemporal Dementia, Progressive Nonfluent Aphasia AD : Uncertain Significance, FTD : Not Classified

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.



Exon 7 Point, Missense
CAT to AAT
0 Shi et al., 2015
M174V
Alzheimer's Disease, Frontotemporal Dementia AD : Benign

Unknown; imaging has shown frontal atrophy and hypoperfusion in temporoparietal regions.

Decreased Aβ40 modestly without significantly changing the Aβ42/Aβ40 ratio in a cell assay.



rs61757781
Exon 7 Point, Missense
ATG to GTG
0 Andreoli et al., 2008;
Clarimón et al., 2008;
Guerreiro et al., 2010
M174I
Alzheimer's Disease AD : Not Classified

Neuropathology consistent with AD. 

Unknown, but in silico algorithm predicted damaging (PHRED-scaled CADD > 20).



Exon 7 Point, Missense
ATG to ATA
0 Wong et al., 2020
S175F
Alzheimer's Disease AD : Not Classified

Unknown, but in one case brain imaging showed atrophy and hypometabolism consistent with AD.

Unknown, but multiple in silico algorithms suggest it is damaging.



Exon 7 Point, Missense
TCT to TTT
0 Guven et al., 2021
S175C
Alzheimer's Disease AD : Not Classified

Unknown; MRI showed focal atrophy in the medial temporal lobe; SPECT showed bilateral hypoperfusion in temporoparietal regions.

Unknown, but in silico analyses predicted a damaging effect (PHRED-scaled CADD score > 20).



rs775145486
Exon 7 Point, Missense
TCT to TGT
0 Piscopo et al., 2010
F183S
Alzheimer's Disease AD : Not Classified

Unknown.

Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score >20). 



Exon 7 Point, Missense
TTC to TCC
0 Wojtas et al., 2012
Y195C
Frontotemporal Dementia FTD : Not Classified

Unknown

Unknown, but the PHRED-scaled CADD score was > 20 suggesting a damaging effect.



rs200410369
Exon 8 Point, Missense
TAC to TGC
0 Koriath et al., 2018
G212V
Alzheimer's Disease AD : Not Classified

Neuropathology consistent with AD.

Unknown; predicted pathogenic in silico (PHRED-scaled CADD score = 27.7).



Exon 8 Point, Missense
GGG to GTG
0 Marín-Muñoz et al., 2016
V214L
Alzheimer's Disease AD : Benign

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; PHRED-scaled CADD score = 24.3.



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).



Exon 8 Point, Missense
CAC to TAC
0 Mao et al., 2021
L225P
Alzheimer's Disease AD : Not Classified

Unknown.

Unknown, but PHRED-scaled CADD score was above 20, suggesting a damaging effect.



rs763295042
Exon 8 Point, Missense
CTG to CCG
0 Koriath et al., 2018
Q228L
Alzheimer's Disease AD : Not Classified

Unknown.

Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score >20).



rs63750880
Exon 8 Point, Missense
CAG to CTG
0 Zekanowski et al., 2003
Y231C
Frontotemporal Dementia FTD : Not Classified

Unknown; MRI showed diffuse subcortical and cortical atrophy, particularly in the frontotemporoparietal lobes.

Unknown but in silico analysis predicted a damaging effect (PHRED-scaled CADD score = 27.8).



Exon 8 Point, Missense
TAC to TGC
0 Marcon et al., 2009
I235F
Alzheimer's Disease, None AD : Not Classified

Unknown.

Increased Aβ42/Aβ40 ratio in cells.



Exon 8 Point, Missense
ATC to TTC
0 Lee et al., 2014
S236S
AD : Benign

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. In silico analyis predicted it is benign (PHRED-scaled CADD = 7.2), but could alter splicing.



rs61730652
Exon 8 Point, Silent
AGT to AGC
0 Coppola et al., 2020
A237V
Alzheimer's Disease AD : Uncertain Significance

Neuropathology consistent with AD.

Unknown; predicted possibly damaging in silico.



rs200670135
Exon 8 Point, Missense
GCG to GTG
0 Sassi et al., 2014
L238F
Alzheimer's Disease AD : Uncertain Significance

Unknown.

Increased Aβ42/Aβ40 ratio in cellular assay.



Exon 8 Point, Missense
CTC to TTC
0 Sala Frigerio et al., 2015
L238P
Alzheimer's Disease AD : Uncertain Significance

Unknown; MRI showed supratentorial cortical atrophy, particularly atrophy of the parietal cortex.

Unknown; predicted damaging in silico (PHRED-scaled CADD score = 26.7).



Exon 8 Point, Missense
CTC to CCC
0 Blauwendraat et al., 2016
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
Exon 8 Point, Missense
ATG to GTG
0 Rogaev et al., 1995
M239T
Alzheimer's Disease AD : Uncertain Significance

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).



Exon 8 Point, Missense
ATG to ACG
0 Li et al., 2021;
Jiao et al., 2021;
Mao et al., 2021
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
Exon 8 Point, Missense
ATG to ATA
0 Finckh et al., 2000
A252T
None AD : Benign

Not applicable.

Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio.



rs138836272
Exon 8 Point, Missense
GCG to ACG
0 Guerreiro et al., 2010
A258T
None AD : Benign

Not applicable.

Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD = 26.8).



rs148238688
Exon 8 Point, Missense
GCC to ACC
0 Sala Frigerio et al., 2015
A258V
Alzheimer's Disease AD : Not Classified

Unknown

Reduced Aβ40 and Aβ42 in a cellular assay without affecting the Aβ42/Aβ40 ratio. 



rs14443227784
Exon 8 Point, Missense
GCC to GTC
0 Yagi et al., 2014
R284G
AD : Likely Pathogenic

Unknown.

Increased Aβ42 and Aβ42/Aβ40 in a cell assay.



rs1208742830
Exon 9 Point, Missense
AGA to GGA
0 Lanoiselée et al., 2017
P287P
AD : Likely Benign

Unknown, but associated with increased glucose metabolism in the bilateral fronto-temporo-parietal cortices.

Unknown, but in silico analysis did not predict a damaging effect (PHRED-scaled CADD = 11.4).



rs75733498
Exon 9 Point, Silent
CCC to CCT
0 Jia et al., 2020
c.887-3C>T
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but in silico analysis does not predict a damaging effect (PHRED-scaled CADD score of 9.977).



rs1230394996
Intron 9 Point
0 Wang et al., 2019
M298T
Alzheimer's Disease AD : Likely Pathogenic

Unknown.

Unknown. Some, but not all, in silico algorithms predicted damaging (PHRED-scaled CADD>20).



rs1482790603
Exon 10 Point, Missense
ATG to ACG
0 Wang et al., 2019
T301M
Alzheimer's Disease AD : Benign

Unknown.

Unchanged Aβ42/Aβ40 ratio.



rs144277432
Exon 10 Point, Missense
ACG to ATG
0 Croes et al., 2004
K306fs
Alzheimer's Disease AD : Not Classified

Unknown; neuroimaging in one case showed cortical atrophy.

Unknown; the deletion of a single nucleotide (A) in exon 9 is predicted to result in a frameshift at codon 306.



Exon 10 Deletion
AAG.CTG to AGC.TGG
0 El Kadmiri et al., 2014
P334A
Alzheimer's Disease, None AD : Benign

Not applicable.

Moderately decreased Aβ40 without changing Aβ42/Aβ40 ratio.



Exon 11 Point, Missense
CCT to GCT
0 Lee et al., 2014
P334R
Alzheimer's Disease, None AD : Benign

Not applicable.

Unknown, but predicted not damaging in silico (PHRED-scaled CADD score = 16.3).



rs63750207
Exon 11 Point, Missense
CCT to CGT
0 Lleó et al., 2002
P348L
Alzheimer's Disease AD : Not Classified

Unknown.

Decreased Aβ40; increased Aβ42/Aβ40 ratio in cell assay.



Exon 11 Point, Missense
CCA to CTA
0 Blauwendraat et al., 2016
G359Lfs*74 (Intron 11 delA)
Alzheimer's Disease, Mild Cognitive Impairment AD : Not Classified, MCI : Not Classified

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.



Intron 11 Point
0 Perrone et al., 2018
G359Lfs*74 (Intron 11 delAG)
Amyotrophic Lateral Sclerosis ALS : Not Classified

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.



Intron 11 Deletion
0 Perrone et al., 2018
I368F
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but multiple in silico algorithms predicted a damaging effect (PHRED-scaled CADD >20).



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)



Exon 12 Point, Missense
TTC to TCC
0 Wan et al., 2021
A377V
Alzheimer's Disease, None AD : Benign

Not applicable.

Unknown.



Exon 12 Point, Missense
GCG to GTG
0 Lee et al., 2014
A379D
Alzheimer's Disease AD : Not Classified

Unknown

Unknown, but predicted damaging in silico. PHREDD CADD score = 27.1



Exon 12 Point, Missense
GCC to GAC
0 Wang et al., 2019
T388M
bvFTD bvFTD : Not Classified

Unknown. CSF biomarker levels (Aβ42, tau, phospho-tau) were not consistent with AD.

Unknown, but multiple in silico algorithms predicted damaging (CADD >20).



rs143549266
Exon 12 Point, Missense
ACG to ATG
0 Ramos-Campoy et al., 2020
C391R
Mild Cognitive Impairment MCI : Not Classified

Unknown.

Unknown, but PHRED-scaled CADD = 28.6, suggesting a deleterious effect.



Exon 12
TGC to CGC
0 Mathioudakis et al., 2023
V393M
Alzheimer's Disease AD : Benign

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

Unknown

Unknown



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).



Exon 13 Point, Missense
GCC to TCC
0 Wong et al., 2020
T421M
Alzheimer's Disease AD : Benign

Unknown

Decreased both Aβ42 and Aβ40, without affecting Aβ42/Aβ40 ratio in cellular assay.



rs756609078
Exon 13 Point, Missense
ACG to ATG
0 Yagi et al., 2014
T430M
Alzheimer's Disease AD : Not Classified

Right frontotemporal hypoperfusion.

Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score = 31).



rs63750666
Exon 13 Point, Missense
ACG to ATG
0 Ezquerra et al., 2003
R435Q
Alzheimer's Disease AD : Uncertain Significance

Unknown.

Unknown, but in silico algorithms predict damaging (PHRED-scaled CADD = 22.1).



rs201922151
Exon 13
CGG to CAG
0
P436L
Alzheimer's Disease Dementia : Not Classified

Unknown, but MRI of one carrier showed bilateral atrophy of the temporal lobe and hippocampus.

Unknown.



Exon 13 Point, Missense
CCG to CTG
0 Han et al., 2020
D439A
Alzheimer's Disease AD : Likely Benign

Unknown; imaging showed moderate cortical atrophy in the frontal and parietal regions.

MIxed results in vitro. 



rs63750110
Exon 13 Point, Missense
GAC to GCC
0 Lleó et al., 2001
c.*71C>A
Alzheimer's Disease AD : Likely Pathogenic

Unknown, but MRI scan of one case showed widening of the sulcus, fissure, and temporal horn, with decreased hippocampal volume. Also, FDG-PET showed hypometabolism in the bilateral frontal, parietal, and temporal lobes. Five affected carriers had CSF Aβ42, total tau, and phospho-tau consistent with AD.

Reduction of binding of PSEN2 expression suppressor miR-183-5p, possibly causing increased Aβ42/Aβ40 ratio.



rs537889666
Exon 13, 3'UTR Point
0 Pang et al., 2021;
Jia et al., 2020