Is HTT p.Arg1654Trp (c.4960C>T) pathogenic?

HTT p.Arg1654Trp (c.4960C>T) is classified Uncertain significance in HTT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-22). AlphaMissense: ambiguous (0.4061); Ultra-rare (popmax 0.0455%, nfe).

How common is HTT p.Arg1654Trp (c.4960C>T) in the general population?

HTT p.Arg1654Trp (c.4960C>T) is ultra-rare (popmax 0.0455%, nfe) (gnomAD).

What do computational predictors say about HTT p.Arg1654Trp (c.4960C>T)?

AlphaMissense predicts ambiguous (score 0.4061) — an in-silico prediction, not a clinical call.

HTT p.Arg1654Trp

c.4960C>T · rs201149918 · VCV871381

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0455%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4061	ambiguous
REVEL	0.339	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.1, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0455% European (non-Finnish) · 537/1,179,616 alleles

Filtering AF 0.0423% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.0368% 594/1,613,560 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0455%	2,197
Admixed American	0.0417%	2,400
Remaining individualsnot grpmax-eligible	0.0336%	2,975
African / African-American	0.008%	12,503
East Asian	0.00446%	22,429
Finnishnot grpmax-eligible	0.00313%	31,991
South Asian	0.0011%	91,060

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HTT
Protein: p.Arg1654Trp
Coding: c.4960C>T
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs201149918
Type: single nucleotide variant
Location: chr4:3186690 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

Full HTT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTT c.889+6G>T Uncertain significance ★★ same type
HTT p.Ala2739Thr Uncertain significance ★★ same type
HTT p.Arg1945Trp Uncertain significance ★★ same type
HTT p.Asp1157Gly Uncertain significance ★★ same type
HTT p.Asp920Asn Uncertain significance ★★ same type
HTT p.Glu449Ala Uncertain significance ★★ ⚠ same type
HTT p.Gly2084Arg Uncertain significance ★★ same type
HTT p.Gly2968Asp Uncertain significance ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/htt-p-arg1654trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown