Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227073369 C>T
dbSNP ID: rs200931244
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6


This mutation was found in a screen of APP, PSEN1, and PSEN2 genes of 148 Chinese patients with familial Alzheimer’s disease (AD) (Gao et al., 2019). Two carriers from two different families were identified: a 74-year-old woman who was 69 at age of onset and an 80-year-old man who was 77 at onset. Both probands suffered from memory loss, disorientation, dyscalculia, and deficits in visuospatial skills. The man also had executive dysfunction and anxiety. The APOE genotype of the woman was APOE3/APOE3, while that of the man was APOE3/APOE4. The variant was reported absent from the gnomAD variant database, but was found at a frequency of 0.00000809 in a more recent database search (two alleles in European individuals, gnomAD v2.1.1, August 2020). 


Biological effect
The biological effect of this mutation is unknown, but in silico algorithms predicted the mutation to be probably damaging (PolyPhen), affecting protein function (SIFT), and disease-causing (MutationTaster), with a CADD score of 35. The authors classified the mutation as “probably pathogenic,” following the algorithm by Guerreiro et al., 2010.


Alzheimer's Disease : Uncertain Significance

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


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


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.

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

Last Updated: 22 Feb 2022


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Paper Citations

  1. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 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.

External Citations

  1. gnomAD v2.1.1, August 2020

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.

Other mutations at this position

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