Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS4, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683951 T>C
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATT to ACT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11


This mutation was identified in a clinical and genetic evaluation of 93 related individuals from a Colombian admixed population (Ramirez Aguilar et al., 2019). The mutation was found to segregate with AD (LOD score of 6). More than a third of the participants (26) were identified as carriers of the mutation. Eight older healthy controls (>55 years) did not carry the variant, and it was absent from the gnomAD variant database (gnomAD v2.1.1, Aug 2021). The associated clinical phenotype is similar to sporadic AD except for earlier age at onset (mean of 47.6 years for MCI and 51.6 years for dementia).

Interestingly, genotypic analyses of the haplotype structure around the mutation indicated the variant occurs on a haplotypic backgound of African origin. The authors note the history of the region includes immigration from Africa in the 17th century as a result of slavery, and admixtures within a confined geographic locale, likely representing a “mini-population bottleneck” and subsequent emergence of a rare dominant mutation. 

Although neuropathological data are unavailable, PET-amyloid and PET-tau scans of two cognitively normal mutation carriers revealed evidence of preclinical amyloid plaques and tau accumulation similar to those reported for individuals at risk for late-onset AD and individuals carrying other AD-causing PSEN1 mutations.

Biological effect
The I416T mutation affects a highly conserved residue in the eighth transmembrane domain of PSEN1, resulting in the substitution of a hydrophobic amino acid with a polar amino acid near a splice site. Ramirez Aguilar and colleagues reported that multiple computational algorithms predicted the mutation is deleterious (Ramirez Aguilar et al., 2019), although, using a slightly different array of algorithms, Xiao and colleagues reported conflicting results (Xiao et al., 2021). The CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

The Ramirez Aguilar group classified this variant as definitely pathogenic according to the Guerreiro algorithm (Guerreiro et al., 2010). 


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.


The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.


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.


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)

Last Updated: 21 Mar 2023


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Paper Citations

  1. . Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 2019 May;15(5):709-719. Epub 2019 Feb 10 PubMed.
  2. . 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.
  3. . 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
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 2019 May;15(5):709-719. Epub 2019 Feb 10 PubMed.

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