Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PP1, BS1, BP4
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73673157 A>G
dbSNP ID: rs115865530
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAA to AGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9


This variant has been found in several individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI). It was first identified in two Chinese men with late-onset AD (LOAD; Dong et al., 2017). Both men were in their 70s when they developed progressive memory decline, and both had a deceased parent who had suffered from similar cognitive impairment at a similar age. The mutation was absent from one cognitively normal family member (unspecified age) and from 100 normal individuals, and 100 unrelated patients with LOAD.

In a subsequent study, the variant was reported in four Chinese pedigrees, two whose affected members had either LOAD or MCI, and two who had only LOAD (Jia et al., 2020). Each family had between three and seven affected members, and between two and four affected mutation carriers, but only one also had an unaffected, non-carrier who was older than the age of onset of the carriers. This non-carrier remained cognitively healthy at age 73, past the ages of AD onset, 65 and 69, of the two known mutation carriers. Across all families, most individuals had an APOE3/E3 genotype, except for three individuals with an APOE3/E2 genotype, and two with an APOE3/E4 genotype. Yet another study reported the mutation in a Han Chinese woman with AD and a family history of dementia (Mao et al., 2021). Her age at onset was 57 years. She had an APOE3/E3 genotype.

The variant was also found in a Vietnamese woman who began experiencing AD symptoms at age 59 (Tong et al., 2021). She was  homozygous for the APOE4 allele. Of 10 family members, only she and her mother, who developed dementia at age 70, were affected.

The variant was present at a frequency of 0.0001344 with an allele count of 38 in the gnomAD variant database (gnomAD v2.1.1, July 2021) and at a frequency of 0.0001439 with an allele count of 33 in the subdivision of the database that excludes data from neurological studies (gnomAD v2.1.1 (non-neuro), July 2021). Of note, most carriers in gnomAD were of East Asian or European ancestry.


Biological Effect
Increased Aβ42 and reduced Aβ40 levels, resulting in an increased Aβ42/Aβ40 ratio, were detected in the conditioned media of cultured cells transfected with plasmids carrying the K311R mutation (Dong et al., 2017). Phosphorylated tau levels were also increased in cell lysates.

However, in silico algorithms (LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, SIFT, Polyphen2, REVEL, PANTHER, Mutpred2 and Reve) yielded conflicting results (Jia et al., 2020Xiao et al., 2021, Mao et al., 2021). Moreover, the variant's PHRED-scaled CADD score was 14.34, below the threshold of 20 often used to predict deleteriousness (CADD v.1.6, Sep 2021). Mao and colleagues classified it as a variant of uncertain significance (Mao et al., 2021).


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.


Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. K311R: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.


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. K311R: At least one family with 2 affected carriers and >=1 unaffected noncarriers.


Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  K311R: Most carriers were of East Asian or European 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.

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. . A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation. J Alzheimers Dis. 2017;57(2):613-623. PubMed.
  2. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
  4. . Genetic analysis of Vietnamese patients with early-onset Alzheimer's disease. Int J Neurosci. 2022 Dec;132(12):1190-1197. Epub 2021 Feb 21 PubMed.
  5. . 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

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation. J Alzheimers Dis. 2017;57(2):613-623. PubMed.

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