Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr21:27284163 C>T
dbSNP ID: rs200088099
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 14


This variant in APP was detected in one out of 376 control cases obtained from the KORA-Age cohort, based in Germany (Schulte et al., 2015). Limited information is available on this subject, but according to a description of the cohort as a whole, all individuals were Caucasian and cognitively healthy at age 65 or older (Schulte et al., 2012).

In the gnomAD database, 51 heterozygous carriers are reported, most from the Latino/Admixed American population (gnomAD version 2.1.1, Oct 2021). Total frequency was 0.0002028.


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). However, the PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, predicting a deleterious effect (CADD v.1.6, Oct 2021). Hsu and colleagues classified this variant as not pathogenic (Hsu et al., 2020).


Alzheimer's Disease : Benign*

*No reported carrier with AD.

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.  T600M: Most carriers are of Latino/Admixed American 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. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  2. . Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease. Neurogenetics. 2012 Aug;13(3):281-5. Epub 2012 Jun 16 PubMed.
  3. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.


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