Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PP3, BS3
Clinical Phenotype Studied: Progressive Supranuclear Palsy
Position: (GRCh38/hg38):Chr17:46024062 G>A
Position: (GRCh37/hg19):Chr17:44101428 G>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs758074229
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CAG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13

Findings

This variant has been identified in two unrelated individuals diagnosed with disorders in the frontotemporal dementia (FTD) spectrum. It was originally reported in a Chinese man diagnosed with FTD (Cheng et al., 2023). His age at onset was 58 years and his primary symptom was memory loss. The carrier reported his father had similar symptoms.

Another male carrier with memory impairment was identified in the U.S. shortly afterwards (Badihian et al., 2024; note the mutation is mistakenly referred to as p.R406W in the title of this paper). This individual developed Richardson’s syndrome, a common form of progressive supranuclear palsy (PSP) at age 62. His symptoms were similar to those of Alzheimer’s disease with poor performance on tests of episodic memory.

In the gnomAD public variant database, this variant was reported at a global frequency of 0.000005, and included eight heterozygotes, six who were of non-Finnish European ancestry (gnomAD v4.1.1, Nov 2025).

Neuropathology
Neuropathological data are unavailable, but MRI imaging of the original proband’s brain revealed mild bilateral frontal and temporal lobe atrophy (Cheng et al., 2023). No amyloid β deposition was identified with PiB-PET.

Also of note, the carrier from the U.S. had elevated levels of tau pathology compared to sporadic PSP patients in bilateral medial temporal lobe regions—amygdala, entorhinal cortex, hippocampus, parahippocampus—but not in PSP-related regions, such as the globus pallidum, midbrain, superior frontal cortex and dentate nucleus of the cerebellum, as revealed by flortaucipir-PET (Badihian et al., 2024).

Biological Effect
This variant has been reported to decrease microtubule binding and assembly, as well as increase tau aggregation (Cheng et al., 2023). In an in vitro assay, a greater proportion of recombinant wildtype tau co-sedimented with microtubules than mutant tau. The recombinant proteins were the 2N4R isoform of tau which harbors four microtubule-binding repeats. In addition, the polymerization rate of tubulin in the presence of mutant 2N4R tau was 40 percent slower than in the presence of wildtype 2N4R tau, and the maximum polymerization was 47 percent lower with the mutant protein. Moreover, mutant 2N4R tau self-aggregated more readily and to a greater extent than wildtype 2N4R, as assessed by thioflavin S fluorescence.

The phosphorylation pattern of mutant tau also appears to differ from that of the wildtype protein, although comparisons were made in transfected HEK293T cells that expressed the two proteins at different levels. Mutant tau was substantially more phosphorylated at T205 and T231 than wildtype tau, and S396 phosphorylation was modestly increased as well. In contrast, S404 was less phosphorylated in cells expressing mutant tau than in those expressing wildtype tau.

Consistent with the above-mentioned findings and the biological effects of another mutation at the same position, R406W, the CADD algorithm predicted R406Q is damaging. R406Q’s PHRED-scaled CADD score, which integrates diverse information in silico, was 25.3, above the commonly used threshold of 20 to predict deleteriousness (gnomAD v4.1.1, Nov 2025). Of note, the arginine at position 406 is evolutionarily highly conserved.

Pathogenicity

Frontotemporal Dementia Spectrum : Uncertain Significance

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

Mutations Citations

1. MAPT R406W

Paper Citations

1. Cheng HR, Lin RR, Li HL, Xue YY, Gao PR, Chen DF, Tao QQ, Wu ZY. Identification and functional characterization of novel variants of MAPT and GRN in Chinese patients with frontotemporal dementia. Neurobiol Aging. 2023 Mar;123:233-243. Epub 2022 Dec 24 PubMed.
2. Badihian N, Ali F, Botha H, Savica R, Machulda MM, Clark HM, Stierwalt JA, Pham NT, Baker MC, Rademakers R, Lowe V, Whitwell JL, Josephs KA. The MAPT p.E342K and p.R406W mutations are associated with progressive supranuclear palsy with atypical features. Parkinsonism Relat Disord. 2024 Feb;119:105962. Epub 2023 Dec 17 PubMed.

Further Reading

No Available Further Reading