Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227083176 G>T
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCC to TCC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13


This variant was found in a whole-exome sequencing screen for rare variants in genes associated with Alzheimer's disease (AD), frontotemporal dementia, and prion disease in a Dutch cohort of 68 patients with early onset AD (Wong et al., 2020).

The proband was a woman who initially presented with memory loss and a spastic gait at age 59. She later developed difficulties with verbal expression, hallucinations, and myoclonus. At 65, she became mute and wheelchair-bound. Her grandmother, aunt, and uncle also had dementia, but their disease onset occurred later, when they were over 65 years old.

This variant was absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathological data are unavailable, but an MRI brain scan of the proband showed global cerebral and cerebellar atrophy (Wong et al., 2020). Moreover, levels of Aβ, phospho-tau, and tau levels, were consistent with AD.

Biological Effect
The biological effect of this variant is unknown, but it is conserved in PSEN1, corresponding to A431, a residue with two pathogenic variants, PSEN1 A431E and A431V. Moreover, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (Wong et al., 2020). Wong and colleagues classified the variant as probably pathogenic using the Guerreiro et al., 2010 guidelines.

Last Updated: 27 Oct 2021


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Mutations Citations

  1. PSEN1 A431E
  2. PSEN1 A431V

Paper Citations

  1. . Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations. Neurobiol Aging. 2019 Jan 29; 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations. Neurobiol Aging. 2019 Jan 29; PubMed.

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