Overview

Pathogenicity: : Not Classified
Position: (GRCh38/hg38):Chr17:45983657 G>A
Position: (GRCh37/hg19):Chr17:44061023 G>A
Transcript: NM_016835; ENST00000571987
dbSNP ID: rs62063786
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to AAC
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, which includes this variant's minor A allele, 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 appears to be protective against these diseases but may predispose carriers to recurrent microdeletion syndromes and some neurodevelopmental disorders such as autism.

This variant was first described in subjects with frontotemporal dementia with parkinsonism-17 and also in healthy controls (Poorkaj et al., 1998) and was later associated with an increased risk of developing progressive supranuclear palsy (PSP) (Higgins et al., 1999).

There is no clear evidence that this common variant contributes 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.

Of note, a large genome-wide association study in individuals of European ancestry identified D285N as associated with increased hemoglobin levels (Oskarsson et al., 2020; GWAS Catalog Sep 2025).

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 (0.00098).

This variant's PHRED-scaled CADD score (6.57), which integrates diverse information in silico, was below the commonly used threshold of 20 to predict deleteriousness (gnomAD v4.1.0, Sep 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.
3. 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.
4. Oskarsson GR, Oddsson A, Magnusson MK, Kristjansson RP, Halldorsson GH, Ferkingstad E, Zink F, Helgadottir A, Ivarsdottir EV, Arnadottir GA, Jensson BO, Katrinardottir H, Sveinbjornsson G, Kristinsdottir AM, Lee AL, Saemundsdottir J, Stefansdottir L, Sigurdsson JK, Davidsson OB, Benonisdottir S, Jonasdottir A, Jonasdottir A, Jonsson S, Gudmundsson RL, Asselbergs FW, Tragante V, Gunnarsson B, Masson G, Thorleifsson G, Rafnar T, Holm H, Olafsson I, Onundarson PT, Gudbjartsson DF, Norddahl GL, Thorsteinsdottir U, Sulem P, Stefansson K. Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis. Commun Biol. 2020 Apr 23;3(1):189. PubMed.

External Citations

1. GWAS Catalog

Further Reading