Mutations

MAPT V289A

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Overview

Pathogenicity: : Not Classified
Clinical Phenotype Studied: None
Position: (GRCh38/hg38):Chr17:45983670 T>C
Position: (GRCh37/hg19):Chr17:44061036 T>C
Transcript: NM_016835; ENST00000571987
dbSNP ID: rs62063787
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTA to GCA
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 4a

Findings

This variant in MAPT exon 4a is one of several single nucleotide polymorphisms used to define the major MAPT H1 and H2 haplotypes. The H1 haplotype has been identified as a risk factor for several neurodegenerative disorders in the frontotemporal dementia (FTD) spectrum, as well as Alzheimer’s disease and Parkinson’s disease (see Pedicone et al., 2024 for review). In contrast, the H2 haplotype, which includes the C allele of this variant, appears to be protective against these diseases but may predispose carriers to recurrent microdeletion syndromes and some neurodevelopmental disorders such as autism.

Originally detected in 22 percent of 95 controls in a study of FTD (Poorkaj et al., 1998), this common variant is not known to contribute causally to neurodegenerative disease risk or expression. Indeed, exon 4a is excluded from the six major tau isoforms expressed in the human brain. Exon 4a is included in PNS-tau, a tau isoform expressed in the peripheral nervous system which is used here as the reference isoform for naming the variant.

In the gnomAD public variant database, this variant was reported at a global frequency of 0.19 (gnomAD v4.1.0, Sep 2025). While it is common in individuals of European ancestry (0.22), it is less frequent in those of African ancestry (0.047), and even less frequent in East Asian populations (0.00096).

This variant's PHRED-scaled CADD score (0.61), which integrates diverse information in silico, was well below the commonly used threshold of 20 to predict deleteriousness (gnomAD v4.1.0, Sep 2025).

Last Updated: 02 Oct 2025

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References

Mutations Citations

  1. MAPT Haplotype H1/H2

Paper Citations

  1. Pedicone C, Weitzman SA, Renton AE, Goate AM. Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases. Mol Neurodegener. 2024 May 29;19(1):43. PubMed.
  2. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.

Further Reading

Papers

  1. Higgins JJ, Adler RL, Loveless JM. Mutational analysis of the tau gene in progressive supranuclear palsy. Neurology. 1999 Oct 22;53(7):1421-4. PubMed.
  2. Higgins JJ, Golbe LI, De Biase A, Jankovic J, Factor SA, Adler RL. An extended 5'-tau susceptibility haplotype in progressive supranuclear palsy. Neurology. 2000 Nov 14;55(9):1364-7. PubMed.
  3. Ingelson M, Fabre SF, Lilius L, Andersen C, Viitanen M, Almkvist O, Wahlund LO, Lannfelt L. Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4. Neuroreport. 2001 Apr 17;12(5):905-9. PubMed.
  4. Stanford PM, Brooks WS, Teber ET, Hallupp M, McLean C, Halliday GM, Martins RN, Kwok JB, Schofield PR. Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies. J Neurol. 2004 Sep;251(9):1098-104. PubMed.

Protein Diagram

Primary Papers

  1. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.

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