Pathogenicity: Alzheimer's Disease : Benign, Parkinson's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3
Clinical Phenotype: Alzheimer's Disease, Parkinson's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27284167 G>A
dbSNP ID: rs140304729
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to AAA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 14


This variant has been found in individuals with neurodegenerative disease, as well as in healthy controls. It was initially reported in an exome-sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls without neuropathology. The variant was detected in one Caucasian control who was at least 60 years of age at death. APOE genotype was E3/E4. Further clinical details were not available (Sassi et al., 2014).

The variant was subsequently detected in one out of 188 cases with Parkinson’s disease, two out of 188 cases with PD with dementia, and one out of 376 controls (Schulte et al., 2015). It was also detected by whole-exome sequencing in two of 424 French people with early onset AD. Clinical details were not reported (Nicolas et al., 2015).

In the gnomAD database, 421 heterozygous carriers and one homozygote are reported (version 2.1.1, Oct 2021). Most of these individuals are from European descent, but the variant is also present in other populations. Total frequency was 0.001492. The variant was also found in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, with an allele count of one in a total of 954 alleles (HEX, Oct 2021).


Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted less Aβ40 compared with cells expressing wild-type APP, but neither the secretion of Aβ42 nor the Aβ42/Aβ40 ratio were significantly altered (Hsu et al., 2020).

Sassi and colleagues reported a possibly damaging prediction from in silico analysis and the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). The variant was classified as a benign polymorphism according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014) and as "not pathogenic" by Hsu and colleagues (Hsu et al., 2020).


Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.


Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  E599K: Most carriers are of European descent.


Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.


Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 15 Mar 2022


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Paper Citations

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. Epub 2014 Jun 16 PubMed.
  2. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  3. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  4. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  5. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Other Citations

  1. HEX

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. Epub 2014 Jun 16 PubMed.


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