Pathogenicity: Alzheimer's Disease : Likely Benign
Clinical Phenotype: Alzheimer's Disease, None
Reference Assembly: GRCh37/hg19
Position: Chr14:73637521 G>A
dbSNP ID: rs63750592
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGG to CAG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


Although this coding variant has been identified in at least two individuals with Alzheimer's disease, it has not been associated with familial disease. Given the lack of evidence for segregation with disease and the fact that the affected residue is not conserved in presenilin-2, this variant is thought to be a rare benign polymorphism.

This variant was detected in one out of 414 Alzheimer's disease patients who were thought to carry genetic risk factors. Segregation analysis was not possible (Rogaeva et al., 2001).

The variant was later found in one Mozabite individual among 130 DNA samples obtained from the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP) (Guerreiro et al., 2010).

Whole-exome sequencing also identified this variant in one of 424 French people with early onset AD. Clinical details were not reported (Nicolas et al., 2015).

The variant is found at a frequency of 0.0001980 with an allele count of 56 in the gnomAD variant database (gnomAD v2.1.1, Sep 2021). In the gnomAD "non-neuro" subset which contains samples from individuals who were not ascertained for having a neurological condition in a neurological case/control study, its frequency is 0.0002050 with an allele count of 47 (gnomAD v2.1.1 (non-neuro), May 2021).


Not applicable.

Biological Effect

In vitro experiments testing the biological effect of this variant have yielded mixed results, showing no change or only a modest elevation of the Aβ42/Aβ40 ratio. An assay using purified proteins to test its ability to cleave the APP-C99 substrate indicated it generates less Aβ40 and Aβ42 than wildtype PSEN1, with a modest elevation of the Aβ42/Aβ40 ratio (Sun et al., 2017). However, a cellular assay using mouse neuroblastoma cells expressing the mutant protein showed secretion of similar amounts of Aβ42 and Aβ40 as cells expressing wild-type PSEN1, with no effect on the Aβ42/Aβ40 ratio (Hsu et al., 2020).

R35 is not conserved between PSEN1 and PSEN2 and in silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021). Hsu and colleagues classified this variant as "not pathogenic" (Hsu et al., 2020).



Last Updated: 15 Sep 2021


No Available Comments

Make a Comment

To make a comment you must login or register.


Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . 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.
  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. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  5. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  6. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1
  2. gnomAD v2.1.1 (non-neuro)

Further Reading


  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.


Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.