Mutations

MAPT D285D

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Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Benign
ACMG/AMP Pathogenicity Criteria: BA1, BS2, BP4
Clinical Phenotype Studied: None
Position: (GRCh38/hg38):Chr17:45983659 C>T
Position: (GRCh37/hg19):Chr17:44061025 C>T
Transcript: NM_016835; ENST00000571987
dbSNP ID: rs63750222
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: GAC to GAT
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 4a

Findings

This variant is likely a benign polymorphism. In the gnomAD public variant database, it was reported at a global frequency of 0.12, with the highest frequency in Admixed Americans and the lowest in individuals of African ancestry (gnomAD v4.1.0, Apr 2024). The variant was originally reported in a study of frontotemporal dementia (FTD) where it was detected in 15 percent of 92 controls screened  (Poorkaj et al., 1998). D285D is located in exon 4a, which 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. This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 0.35, well below the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, April 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

BA1

Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 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: 30 Oct 2025

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References

Paper Citations

  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.

Further Reading

Papers

  1. Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat. 2004 Oct;24(4):277-95. PubMed.
  2. 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.

Other mutations at this position

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Alzpedia

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