Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685869 G>C
dbSNP ID: rs63751223
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to CCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12


This mutation was first identified in a Scottish-Irish kindred with familial AD (Poorkaj et al., 1998). Six affected members had an average age of onset of 46 years. The mutation was found in both of the affected individuals tested, as well as in three at-risk individuals under the age of 51. It was absent from 200 controls. In a subsequent study of this kindred, five mutation carriers were identified, all of whom had either mild cognitive impairment (MCI) or AD, with ages of onset from 35-44 years (Klunk et al., 2007). An unaffected, non-carrier sibling had normal cognition and no sign of amyloid accumulation as assessed by PET imaging at age 47. Although this sibling's age was close to the end of the range of disease onset, their lack of amyloid indicates they were unlikely to develop symptoms for many more years. 

The mutation was also found in a 57-year-old without a clear family history of dementia in a screen of individuals with extreme CSF Aβ42, tau or phosphorylated tau levels (Benitez et al., 2013).

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

Neuropathology data are unavailable, but PiB-PET imaging of three mutation carriers with MCI and two with AD revealed amyloid deposition that differed from that observed in typical, sporadic AD (Klunk et al., 2007). Amyloid accumulation was particularly prominent in the striatum, and also observed in the neocortex and thalamus. The two individuals diagnosed with AD had lower PiB retention in frontal, temporoparietal, and precuneus cortices than most very mildly impaired sporadic AD patients.

Biological Effect

Amyloid β production was disrupted in HEK293 cells expressing this variant, as reported in a preprint (Schultz et al., 2023). While the Aβ42/Aβ40 ratio was increased, the ratio of short to long Aβ species was decreased, indicating a damaging effect. An indicator of γ-secretase function as a percentage of wildtype activity was developed combining the Aβ (37 + 38 + 40) / (42 + 43) ratio—a measure of γ-processivity—with the commonly used Aβ42/Aβ40 ratio—a measure of the relative production of aggregation-prone Aβ. This composite score, 52.86 for A426P, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate found slightly lower amounts of Aβ40 and Aβ42 production compared with the wildtype protein, and no effect on the Aβ42/Aβ40 ratio (Sun et al., 2017). However, this assay's ability to recapitulate physiological cleavage efficiency appears to be limited (Liu et al., 2021).

The mutation site is conserved in PSEN1, PSEN2, mouse PSEN1, and sel-12. Although one study reported in silico SIFT analysis predicted it to be tolerated, whereas Polyphen2 classified it as probably damaging (Benitez et al., 2013), another study, using additional in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) reported consistent results predicting this variant is damaging (Xiao et al., 2021).


Alzheimer's Disease : Pathogenic

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. A426P: Although an in vitro assay failed to detect an effect, a more extensive, cell-based survey of Aβ peptide production revealed a clear-cut functional effect.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.


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.


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. A426P: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


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)

Research Models

A non-human primate model of AD carrying this variant has been created using CRISPR/Cas9 technology in marmosets (Sukoff Rizzo et al., 2023).

Last Updated: 24 Aug 2023


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Paper Citations

  1. . Bridging the rodent to human translational gap: Marmosets as model systems for the study of Alzheimer's disease. Alzheimers Dement (N Y). 2023;9(3):e12417. Epub 2023 Aug 21 PubMed.
  2. . Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
  3. . Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.
  4. . The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.
  5. . Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
  6. . 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.
  7. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
  8. . 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

Further Reading

Protein Diagram

Primary Papers

  1. . Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.


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