21-25897642-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS2

The NM_000484.4(APP):c.1995G>C(p.Glu665Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

APP
NM_000484.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4O:1

Conservation

PhyloP100: 1.92

Publications

9 publications found

Variant links:

Genes affected

APP (HGNC:620): (amyloid beta precursor protein) This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]

APP Gene-Disease associations (from GenCC):

Alzheimer disease type 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
cerebral amyloid angiopathy, APP-related
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
ABeta amyloidosis, Arctic type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, dutch type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, Iowa type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, Italian type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABetaA21G amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABetaL34V amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset autosomal dominant Alzheimer disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

APP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000484.4

BS2

High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4 link	c.1995G>C	p.Glu665Asp	missense_variant	Exon 16 of 18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8 link	c.1995G>C	p.Glu665Asp	missense_variant	Exon 16 of 18	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251368

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111828

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other:1

Mar 14, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The E665D variant in the APP gene has been reported previously in the heterozygous state in a woman with late-onset Alzheimer disease; however further evidence supporting pathogenicity was not provided (Peacock et al., 1994). Additionally, this variant was not present in this individual's son with memory problems and other medical issues, but was observed in an asymptomatic relative who was over the age of 65 (Peacock et al., 1994). The E665D variant is observed in 1/66730 (0.0015%) alleles from individuals of European (Non-Finnish) background, in the ExAC dataset (Lek et al., 2016). The E665D variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E665D as a variant of uncertain significance, -

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Alzheimer disease type 1

Pathogenic:1

Apr 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

Jun 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: APP c.1995G>C (p.Glu665Asp) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 1.2e-05 in 251368 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1995G>C has been observed in individual(s) affected with Alzheimers disorders (Peacock_1994, Abbatemarco_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cerebral Amyloid Angiopathy, APP-Related. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in N2A cells (Hsu_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33445953, 32087291, 8154870). ClinVar contains an entry for this variant (Variation ID: 18095). Based on the evidence outlined above, the variant was classified as uncertain significance. -

APP-related disorder

Uncertain:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The APP c.1995G>C variant is predicted to result in the amino acid substitution p.Glu665Asp. This variant was reported in an individual with late-onset Alzheimer's disease (AD) (Peacock et al. 1994. PubMed ID: 8154870). It was also reported in an individual with early-onset progressive cognitive and behavioral dysfunction and markers in the cerebrospinal fluid (CSF) consistent with Alzheimer's disease (Abbatemarco et al. 2021. PubMed ID: 33445953). In a functional study, it was reported not to increase levels of Aβ42/40 or Aβ42, and was considered not pathogenic (Hsu et al. 2020. PubMed ID: 32087291). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Alzheimer disease

Uncertain:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect APP function (PMID: 32087291). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APP protein function. ClinVar contains an entry for this variant (Variation ID: 18095). This missense change has been observed in individual(s) with clinical features of APP-related conditions (PMID: 8154870, 33445953). This variant is present in population databases (rs63750363, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 665 of the APP protein (p.Glu665Asp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.;.;.;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.041

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.57

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.7

L;.;.;.;.;.;.;.

PhyloP100

1.9

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.42

N;N;N;N;.;N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.56

T;T;T;T;.;T;T;T

Sift4G

Benign

0.40

T;T;T;T;T;T;T;T

Polyphen

0.21

B;B;P;P;.;.;B;.

Vest4

0.83

MutPred

0.71

Loss of disorder (P = 0.1673);.;.;.;.;.;.;.;

MVP

0.81

MPC

0.42

ClinPred

0.25

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.57

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over