Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: PP1, BS1, BP4, BP5
Reference Assembly: GRCh37/hg19
Position: Chr1:227077809 C>T
dbSNP ID: rs75733498
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: CCC to CCT
Reference Isoform: PSEN2 (Human)
Genomic Region: Exon 9


This common synonymous variant was found in four families of the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). In total, six affected carriers were reported with variable ages at onset, ranging from 48 to 70 years. In one family, the variant appeared to cosegregate with disease, including one affected carrier with age at onset of 68, and three unaffected non-carriers aged 73 to 76. However, the affected carrier was an APOE4 homozygote, while the three unaffected, non-carriers were APOE4 heterozygotes. Also, in all four families, affected carriers had at least one APOE4 allele, three of whom were homozygotes.

This variant was also reported as being associated with increased metabolism in brain regions affected by AD (see Neuropathology below, Seo et al., 2020). 

The frequency of this variant is 0.083 in the KBASE cohort and 0.016 worldwide (gnomAD v2.1.1, Nov 2021). In the gnomAD database, it is particularly prevalent in individuals of Asian or Latino/Admixed American ancestry.


Neuropathology data are unavailable, but as noted above, the variant has been reported as being associated with increased cerebral glucose metabolism in regions typically affected by AD (Seo et al., 2020). The study examined 274 cognitively normal adults 55 years or older, 137 individuals with mild cognitive impairment, and 94 patients with AD dementia from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). FDG-PET analysis revealed non-carriers had reduced glucose metabolism levels in the bilateral fronto-temporo-parietal cortices (P < 0.01, k = 1497). The odds ratio of the association was 0.39 (95 percent CI 0.23–0.63; P = 1.8 × 10−4). An association with brain FDG-uptake was also found in an elderly Korean cohort of 4683 individuals (P = 1.6 × 10−4).

Biological Effect

The biological effects of this variant are unknown, but it probably has no impact on splicing (Jia et al., 2020) and its PHRED-scaled CADD score, which integrates diverse information in silico, was well below 20 (11.4), suggesting it does not have a damaging effect (CADD v.1.6, Nov 2021). 


Alzheimer's Disease : Likely Benign*

*This variant may be a disease modifier, a classification not included in the ACMG-AMP guidelines.

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


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion.


Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  P287P: Most carriers were of Asian or Latino/Admixed American ancestry.


Multiple lines of computational evidence suggest no impact on 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 less than 20.


Variant found in a case with an alternate molecular basis for disease. P287P: 3 of 4 affected carriers were APOE4 homozygotes and the fourth was an APOE4 heterozygote.

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. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  2. . Genetic associations of in vivo pathology influence Alzheimer's disease susceptibility. Alzheimers Res Ther. 2020 Nov 19;12(1):156. PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.

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