Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: None, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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).


Not applicable.

Biological Effect

Although this variant is predicted to be benign by in silico analysis, an in vitro assay using purified proteins to test its ability to cleave the APP-C99 substrate revealed it generates less Aβ40 and Aβ42 than wildtype PSEN1, resulting in a modestly elevated Aβ42/Aβ40 ratio (Sun et al., 2017).

Last Updated: 27 Aug 2019


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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.

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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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.


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