Mutations

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APP (58)

APP encodes amyloid precursor protein, a transmembrane protein which is cleaved to form amyloidogenic Aβ peptides. Mutations in APP are associated with familial forms of early onset Alzheimer's disease as well as with Cerebral Amyloid Angiopathy (CAA). Pathogenic mutations generally alter processing by secretases, leading in an overall increase in Aβ production and/or a change in the ratio of specific Aβ peptides.

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
A201V
None, Parkinson's Disease Dementia AD : Not Pathogenic Not applicable. Unknown; predicted tolerated in silico.

rs149995579
Coding
Exon 5
Point, Missense
GCG to GTG
0 Sassi et al., 2014
A235V
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 6
Point, Missense
GCT to GTT
0 Nicolas et al., 2015
D243N
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 6
Point, Missense
GAT to AAT
0 Nicolas et al., 2015
E246K
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; predicted probably damaging in silico.

rs147485129
Coding
Exon 6
Point, Missense
GAG to AAG
0 Sala Frigerio et al., 2015
E296K
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 7
Point, Missense
GAG to AAG
0 Nicolas et al., 2015
P299L
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 7
Point, Missense
CCG to CTG
0 Nicolas et al., 2015
R468H
None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 11
Point, Missense
CGC to CAC
0 Schulte et al., 2015
A479S
None AD : Not Pathogenic Not applicable. Unknown; predicted benign in silico.

rs143794560
Coding
Exon 11
Point, Missense
GCT to TCT
0 Sala Frigerio et al., 2015
K496Q
Alzheimer's Disease AD : Unclear Pathogenicity One reported carrier of this variant had autopsy-confirmed AD. Unknown; predicted possibly damaging in silico.

rs201384815
Coding
Exon 12
Point, Missense
AAG to CAG
0 Sassi et al., 2014
A500T
None AD : Not Pathogenic Not applicable. Unknown.

rs201547994
Coding
Exon 12
Point, Missense
GCA to ACA
0 Schulte et al., 2015
Y538H
Alzheimer's Disease AD : Not Pathogenic Neuropathology consistent with AD, but not thought to be attributed to this variant. Unknown; predicted possibly damaging in silico.

Coding
Exon 13
Point, Missense
TAT to CAT
0 Sassi et al., 2014
V562I
None AD : Not Pathogenic Not applicable. Unknown; predicted tolerated in silico.

rs199586073
Coding
Exon 13
Point, Missense
GTT to ATT
0 Sassi et al., 2014
E599K
None, Parkinson's Disease, Parkinson's Disease Dementia AD : Not Pathogenic Not applicable. Unknown; predicted possibly damaging in silico.

rs140304729
Coding
Exon 14
Point, Missense
GAA to AAA
0 Sassi et al., 2014
T600M
None AD : Not Pathogenic Not applicable. Unknown.

rs200088099
Coding
Exon 14
Point, Missense
ACG to ATG
0 Schulte et al., 2015
P620A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 14
Point, Missense
CCG to GCG
0 Nicolas et al., 2015
P620L
Alzheimer's Disease AD : Not Pathogenic One reported carrier of the variant had autopsy-confirmed AD.  Unknown; predicted tolerated in silico.

Coding
Exon 14
Point, Missense
CCG to CTG
0 Sassi et al., 2014
T663M
Parkinson's Disease Dementia AD : Not Pathogenic, PDD : Unclear Pathogenicity Unknown. Unknown.

rs200260102
Coding
Exon 16
Point, Missense
ACG to ATG
0 Schulte et al., 2015
E665D
None AD : Not Pathogenic Not applicable. Unknown.

rs63750363
Coding
Exon 16
Point, Missense
GAG to GAC
0 Peacock et al., 1994
KM670/671NL
(Swedish)
Alzheimer's Disease AD : Pathogenic Generalized atrophy with sulcal widening and mild ventricular enlargement. Increased total Aβ; unchanged Aβ42/Aβ40 ratio; increased production and secretion of Aβ42 and Aβ40.

rs63751263, rs63750445
Coding
Exon 16
Point, Double
AAG.ATG to AAT.CTG
49 Mullan et al., 1992
A673T
(Icelandic)
None AD : Protective This variant is associated with minimal amyloid deposition and is thought to protect against amyloid pathology. Reduced production of amyloidogenic Aβ peptides by about 40 percent. The Aβ generated is less prone to aggregation.

rs63750847
Coding
Exon 16
Point, Missense
GCA to ACA
0 Peacock et al., 1993;
Jonsson et al., 2012
A673V
Alzheimer's Disease AD : Pathogenic Definite AD by CERAD criteria, with extensive deposition of Aβ and tau pathology (Braak stage VI). Cerebral amyloid angiopathy. Deposits contained high levels of Aβ40 and were noted to be unusually large, with few preamyloid deposits. Localization was frequently perivascular. In vitro, A673V shifts β-secretase processing of APP toward the amyloidogenic pathway and increases Aβ aggregation; however, co-incubation of mutant and wild-type Aβ inhibits amyloidogenesis and toxicity.

Coding
Exon 16
Point, Missense
GCA to GTA
0 Di Fede et al., 2009
H677R
(English)
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.

63749953
Coding
Exon 16
Point, Missense
CAT to CGT
0 Janssen et al., 2003
D678H
(Taiwanese)
Alzheimer's Disease AD : Pathogenic Unknown; SPECT imaging showed hypoperfusion in the bilateral parietal cortices and the left temporal lobe. Increased Aβ42/Aβ40 ratio in conditioned media; increased secreted Aβ42 and Aβ40. When coincubated with Cu2+ and Zn2+, mutant Aβ exhibits increased metal ion binding and formation of ion-induced Aβ oligomers. Increased toxicity in vitro compared with wild-type Aβ42.

Coding
Exon 16
Point, Missense
GAC to CAC
0 Chen et al., 2012
D678N
(Tottori)
Alzheimer's Disease AD : Pathogenic Marked cortical atrophy, Bilateral hippocampal atrophy, Absence of focal cerebral infarction or hemorrhagic lesions. Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.

rs63750064
Coding
Exon 16
Point, Missense
GAC to AAC
0 Wakutani et al., 2004
E682K
(Leuven)
Alzheimer's Disease AD : Pathogenic Bilateral hippocampal volume loss; Cortical PiB uptake. Significantly increased total Aβ and Aβ42/Aβ40 levels; Shifts BACE1 cleavage toward the β-site.

Coding
Exon 16
Point, Missense
GAA to AAA
0 Zhou et al., 2011
K687N
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed mild global brain atrophy without focal or vascular lesions. CSF biomarker profile consistent with AD, specifically elevated total tau and phosphorylated tau, along with reduced levels of Aβ1-42. Reduces APP cleavage by α-secretase. Reduced production of total sAPP and especially sAPPα. Increased Aβ40 and Aβ42. Alone, mutant Aβ was less toxic to neuroblastoma cells than wild-type Aβ42, but mixed in equimolar amounts with wild-type, toxicity increased. Alone, mutant Aβ formed predominantly low-n oligomers in vitro, but mixed with wild-type Aβ, it aggregated into high-n oliogmers.

Coding
Exon 16
Point, Missense
AAA to AAT
0 Kaden et al., 2012
A692G
(Flemish)
Alzheimer's Disease AD : Pathogenic β-amyloid deposition in the blood vessels of the brain; Numerous senile plaques; Dystrophic neurites; Congophilic angiopathy; Hemorrhagic infarction. Increased secreted Aβ42 and Aβ40 in CHO, HEK-293, and H4 cells; Altered APP processing.

rs63750671
Coding
Exon 17
Point, Missense
GCA to GGA
0 Hendriks et al., 1992
E693del
(Osaka, E693∆, E693delta)
Alzheimer's Disease AD : Pathogenic Unknown; remarkably low levels of amyloid by PiB-PET imaging. Unchanged Aβ42/Aβ40 ratio; decreased Aβ42; decreased Aβ40; Mutant Aβ more resistant to degradation by neprilysin and insulin-degrading enzyme; Synthetic mutant Aβ had enhanced oligomerization but no fibrillization; Greater inhibition of LTP than wild-type Aβ.

Coding
Exon 17
Deletion
GAA to ---
1 Tomiyama et al., 2008
E693G
(Arctic, E22G)
Alzheimer's Disease AD : Pathogenic No signs of strokes or vascular lesions by brain imaging; Neuritic plaques and neurofibrillary tangles. Arctic Aβ40 forms protofibrils at an increased propensity and faster rate; Decreased proteolytic degradation of Aβ by neprilysin.

rs63751039
Coding
Exon 17
Point, Missense
GAA to GGA
5 Kamino et al., 1992;
Nilsberth et al., 2001
E693K
(Italian)
Cerebral Amyloid Angiopathy CAA : Pathogenic Small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts; Aβ immunoreactivity in vessel walls and neuropil; Absence of neurofibrillary changes and neuritic plaques. Reduced Aβ42/Aβ40 ratio; decreased Aβ42; comparable Aβ40 to wild-type APP.

rs63750579
Coding
Exon 17
Point, Missense
GAA to AAA
0 Tagliavini et al., 1999;
Bugiani et al., 2010
E693Q
(Dutch)
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type CAA : Pathogenic Extensive amyloid deposition in the cerebral vasculature; Hemorrhages; Some diffuse plaques in brain parenchyma. Accelerates Aβ aggregation in vitro, increasing fibril formation; Alters the processing of APP, increasing the relative quantities of Aβ beginning at Asp1, Val18, and Phe19.

rs63750579
Coding
Exon 17
Point, Missense
GAA to CAA
4 Levy et al., 1990;
Van Broeckhoven et al., 1990;
Fernandez-Madrid et al., 1991
D694N
(Iowa)
Alzheimer's Disease, Cerebral Amyloid Angiopathy AD : Pathogenic, CAA : Pathogenic Extensive cerebral amyloid angiopathy; Widespread neurofibrillary tangles; Abundant Aβ40 in plaques; Hemorrhagic lesions; Cortical calcifications in the occipital lobe. Increased fibrillogenesis of the Aβ peptide; Greater Aβ-induced toxicity.

rs63749810
Coding
Exon 17
Point, Missense
GAT to AAT
2 Grabowski et al., 2001
L705V
Cerebral Amyloid Angiopathy CAA : Pathogenic Severe CAA; Hemorrhages originating from affected vessels; “Vessel-within-vessel” morphology; Absence of parenchymal amyloid deposits and neurofibrillary tangles. Unknown.

rs63750921
Coding
Exon 17
Point, Missense
CTC to GTC
0 Obici et al., 2005
G708G
None AD : Not Pathogenic Not applicable. Unknown.

rs148888161
Coding
Exon 17
Point, Silent
GGC to GGT
0 Balbín et al., 1992
G709S
Parkinson's Disease Dementia AD : Not Pathogenic, PDD : Unclear Pathogenicity Unknown. Unknown.

rs201269325
Coding
Exon 17
Point, Missense
GGT to AGT
0 Schulte et al., 2015
A713T
Alzheimer's Disease, Cerebral Amyloid Angiopathy, None AD : Pathogenic, CAA : Pathogenic Variable: Generalized atrophy of the cerebral cortex; Widespread neurofibrillary tangles; Neuritic plaques; Variable cerebral amyloid angiopathy. Unchanged Aβ42/Aβ40 ratio in postmortem brain.

rs63750066
Coding
Exon 17
Point, Missense
GCG to ACG
0 Carter et al., 1992;
Armstrong et al., 2004
A713V
None AD : Not Pathogenic Not applicable. Unknown.

rs1800557
Coding
Exon 17
Point, Missense
GCG to GTG
0 Jones et al., 1992
T714A
(Iranian)
Alzheimer's Disease AD : Pathogenic Progressive cortical atrophy; White matter lesions. Unknown.

rs63750643
Coding
Exon 17
Point, Missense
ACA to GCA
0 Pasalar et al., 2002
T714I
(Austrian)
Alzheimer's Disease AD : Pathogenic Extensive neuronal loss; Diffuse gliosis; Neurofibrillary tangles; Amyloid plaques including diffuse "cloudy" plaques. Increased Aβ42/Aβ40 ratio (about 11-fold); increased Aβ42; decreased Aβ40.

rs63750973
Coding
Exon 17
Point, Missense
ACA to ATA
1 Kumar-Singh et al., 2000
V715A
(German)
Alzheimer's Disease AD : Pathogenic Hypoperfusion in the parieto-occipital region. Increased Aβ42/Aβ40 ratio.

rs63750868
Coding
Exon 17
Point, Missense
GTG to GCG
0 Cruts et al., 2003
V715M
(French)
Alzheimer's Disease AD : Pathogenic Progressive cortical atrophy; Hypometabolism. Decreased total Aβ; unchanged Aβ42; significantly decreased Aβ40.

rs63750734
Coding
Exon 17
Point, Missense
GTG to ATG
0 Ancolio et al., 1999
I716F
(Iberian)
Alzheimer's Disease AD : Pathogenic Extensive mixed neuropathology, including neurofibrillary changes, amyloid deposits, and Lewy bodies. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40; Increased APP C-terminal fragments; Decreased production of APP intracellular domain.

Coding
Exon 17
Point, Missense
ATC to TTC
2 Guerreiro et al., 2010
I716M
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed mild bilateral hippocampal atrophy. Unknown; predicted damaging in silico.

Coding
Exon 17
Point, Missense
ATC to ATG
0 Blauwendraat et al., 2016
I716T
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750851
Coding
Exon 17
Point, Missense
ATC to ACC
0 Terreni et al., 2002
I716V
(Florida)
Alzheimer's Disease AD : Pathogenic Diffuse cortical atrophy, most prominant in the left anterior temporal lobe. Increased Aβ42(43)/Aβ40 ratio; increased Aβ42(43).

rs63750399
Coding
Exon 17
Point, Missense
ATC to GTC
1 Eckman et al., 1997
V717F
(Indiana)
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42/Aβ40 ratio.

rs63750264
Coding
Exon 17
Point, Missense
GTC to TTC
10 Murrell et al., 1991
V717G
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in at least one case. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63749964
Coding
Exon 17
Point, Missense
GTC to GGC
0 Chartier-Harlin et al., 1991
V717I
(London)
Alzheimer's Disease AD : Pathogenic Variable: some reports of mild amyloid angiopathy and cortical and brainstem Lewy bodies, along with numerous plaques and tangles. Increased Aβ42/Aβ40 ratio; increased Aβ42; little effect on Aβ40.

rs63750264
Coding
Exon 17
Point, Missense
GTC to ATC
12 Goate et al., 1991
V717L
Alzheimer's Disease AD : Pathogenic Unknown; MRI in the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63750264
Coding
Exon 17
Point, Missense
GTC to CTC
0 Murrell et al., 2000
T719P
Alzheimer's Disease AD : Pathogenic Unknown; atrophy of the temporal lobes by MRI. Reduced total Aβ in CSF, especially Aβ1-40 and Aβ1-42 with a relative increase in Aβ1-38.

Coding
Exon 17
Point, Missense
ACC to CCC
0 Ghidoni et al., 2009
M722K
Alzheimer's Disease, None AD : Pathogenic Unknown; MRI of the proband at age 42 showed moderate cerebral atrophy, especially in the hippocampus. Increase Aβ42/Aβ40 ratio; increased Aβ42; unchanged Aβ40; More phospho-tau.

Coding
Exon 17
Point, Missense
ATG to AAG
0 Wang et al., 2015
L723P
(Australian)
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42 in CHO cells.

rs63751122
Coding
Exon 17
Point, Missense
CTG to CCG
0 Kwok et al., 2000
K724N
(Belgian)
Alzheimer's Disease AD : Pathogenic Significant amyloid across the cerebral cortex as measured by PiB-PET. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63750151
Coding
Exon 17
Point, Missense
AAG to AAC
0 Theuns et al., 2006
H733P
None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 17
Point, Missense
CAT to CCT
0 Guerreiro et al., 2010
IVS17 83-88delAAGTAT
Alzheimer's Disease, None AD : Unclear Pathogenicity Unknown; at least one affected deletion carrier had neuropathology consistent with AD. Unknown; deletion does not appear to affect APP splicing.

rs367709245
Non-Coding
Intron 17
Deletion
0 Kamino et al., 1992
c.*18 C>T
Cerebral Amyloid Angiopathy CAA : Unclear Pathogenicity Unknown; imaging showed an ischemic stroke in the right middle cerebral artery and hematomas in the right temporal and parietal lobes. MRI showed numerous cortical microbleeds and  white-matter hyperintensities. Unknown.

rs201729239
Non-Coding
3' UTR
Point
0 Nicolas et al., 2015
c.*331_*332del
Cerebral Amyloid Angiopathy CAA : Pathogenic Unknown; imaging revealed multiple subarachnoid hemorrhages and hematomas in the temporal, frontal, and parietal regions of the cortex, as well as diffuse superficial siderosis, cortical microbleeds, and white matter hyperintensities. This deletion of two base pairs (TA) occurs in a highly conserved region of  the UTR. When cloned into a luciferase reporter, the variant increased APP expression (~1.5-fold over WT). APP upregulation was at least partially attributable to changes in miRNA binding.

Non-Coding
3' UTR
Deletion
0 Nicolas et al., 2015
c.*372 A>G
Cerebral Amyloid Angiopathy CAA : Not Pathogenic Unknown; at least two mutation carriers had hemorrhages and microbleeds consistent with CAA. However, this variant has also been detected in controls. Unknown.

rs187940037
Non-Coding
3' UTR
Point
0 Nicolas et al., 2015