Mutations

MAPT P4T

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr17:45962347 C>A
Position: (GRCh37/hg19):Chr17:44039713 C>A
dbSNP ID: rs974837695
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCC to ACC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 1

Findings

This variant was detected in a control individual in a study assessing 72 AD cases and 58 controls (Sala Frigerio et al., 2015). The age of the mutation carrier was not reported, nor were details regarding his or her cognitive health. Classification as a control was based on a lack of significant AD pathology in the brain.

In the gnomAD variant database, the variant was present at a global frequency of 0.000012, including 20 heterozygotes (gnomAD v4.1.0, Apr 2024). The highest frequency was in individuals of admixed American ancestry.

Neuropathology

Not applicable.

Biological Effect

This variant has been reported to increase the translation of mRNA tau species with short 5’ UTRs (De Costa et al., 2024). Interestingly, these 5’ truncated mRNAs appear to be overexpressed in AD and PSP brains (Huin et al., 2017). 

In silico, the P4T variant was predicted to be probably damaging by PolyPhen2 (Sala Frigerio et al., 2015). Moreover, its PHRED-scaled CADD score, which integrates multiple in silico data, was 28.8, above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, April 2024).

Last Updated: 18 Feb 2025

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References

Paper Citations

  1. da Costa J, Perret, Buée, Hamdane, Martin. FTLD-MAPT mutations and short 5 UTR Tau mRNAs increase Tau translation. NAR Molecular Medicine, Volume 1, Issue 4, October 2024 Published: 10 December 2024 https://doi.org/10.1093/narmme/ugae023
  2. Huin V, Buée L, Behal H, Labreuche J, Sablonnière B, Dhaenens CM. Alternative promoter usage generates novel shorter MAPT mRNA transcripts in Alzheimer's disease and progressive supranuclear palsy brains. Sci Rep. 2017 Oct 3;7(1):12589. PubMed.

Other Citations

  1. Sala Frigerio et al., 2015

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.

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