Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Benign, Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: BA1, BS2, BP4
Clinical Phenotype Studied: Alzheimer's Disease, Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:45990016 T>C
Position: (GRCh37/hg19):Chr17:44067382 T>C
Transcript: NM_016835; ENST00000571987
dbSNP ID: rs2258689
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TAC to CAC
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 6

Findings

This common genetic variant may modify the risk of Alzheimer’s disease (AD) and a psychological trait. The variant resides in exon 6, which is excluded from the major tau isoforms expressed in the human brain, but 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.

Y441H, originally referred to as H47Y or His47Tyr, was described as a likely benign polymorphism due to its presence in families with frontotemporal dementia (FTD), as well as in healthy controls (Poorkaj et al., 1998). Indeed, as reported in the gnomAD public variant database, the minor allele C (encoding histidine) is carried by approximately a quarter of individuals worldwide and is particularly prevalent in individuals of East Asian ancestry, where it has been reported at a frequency of 0.60 (gnomAD v.4.1.0, Apr 2024).

However, the variant may be a risk modifier for certain conditions. A relatively small study of 721 Chinese AD patients and 1,391 controls reported elevated AD risk in carriers of the T allele (encoding tyrosine) (OR=1.27; CI = 1.11–1.46; adjusted p-value = 1.86 × 10^-3; Xiao et al., 2021). Moreover, a genome-wide association study including approximately 1.5 million individuals of European ancestry found the T allele associated with a decreased risk of externalizing behaviors—behaviors related to impaired self-regulation, such as aggression, defiance, and impulsivity (β = 0.008 unit decrease, CI = [0.006-0.01], p-value = 2 x 10^-8; GWAS catalog, Jul 2025; Karlsson et al., 2021).

Biological Effect
The biological effect of this variant is unknown. Its PHRED-scaled CADD score, which integrates diverse information in silico, was 15.9, below the commonly used threshold of 20 for predicting deleteriousness (gnomAD v.4.1.0, Apr 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.

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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.
2. Xiao X, Yuan Z, Guo L, Liao X, Zhou Y, Zhang W, Zhou L, Wang X, Liu X, Liu H, Wang J, Li J, Shen L, Jiao B. The role of frontotemporal dementia associated genes in patients with Alzheimer's disease. Neurobiol Aging. 2021 Nov;107:153-158. Epub 2021 May 30 PubMed.
3. Karlsson Linnér R, Mallard TT, Barr PB, Sanchez-Roige S, Madole JW, Driver MN, Poore HE, de Vlaming R, Grotzinger AD, Tielbeek JJ, Johnson EC, Liu M, Rosenthal SB, Ideker T, Zhou H, Kember RL, Pasman JA, Verweij KJ, Liu DJ, Vrieze S, COGA Collaborators, Kranzler HR, Gelernter J, Harris KM, Tucker-Drob EM, Waldman ID, Palmer AA, Harden KP, Koellinger PD, Dick DM. Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction. Nat Neurosci. 2021 Oct;24(10):1367-1376. Epub 2021 Aug 26 PubMed.

External Citations

1. GWAS catalog

Further Reading