Is HTT p.Arg2015Trp (c.6043C>T) pathogenic?

HTT p.Arg2015Trp (c.6043C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-10). AlphaMissense: likely pathogenic (0.8807); Very rare (popmax 0.00356%, nfe).

How common is HTT p.Arg2015Trp (c.6043C>T) in the general population?

HTT p.Arg2015Trp (c.6043C>T) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about HTT p.Arg2015Trp (c.6043C>T)?

AlphaMissense predicts likely pathogenic (score 0.8807) — an in-silico prediction, not a clinical call.

HTT p.Arg2015Trp

c.6043C>T · rs752705093 · VCV1523682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Computational evidence

Protein change
AlphaMissense	0.8807	likely pathogenic
REVEL	0.344	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 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 0.00356% European (non-Finnish) · 42/1,179,578 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00298% 48/1,612,606 alleles · very rare exomes 46/1,460,516 · genomes 2/152,090 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,085
South Asian	0.00331%	30,253
East Asian	0.00223%	44,878
Remaining individualsnot grpmax-eligible	0.0016%	62,430
African / African-American	0.00134%	74,804

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.Arg2015Trp
Coding: c.6043C>T
MANE Select: NM_001388492
dbSNP: rs752705093
Type: single nucleotide variant
Location: chr4:3206951 (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 p.Arg2015Gln Uncertain significance ★ same residue
HTT c.889+6G>T Uncertain significance ★★ same type
HTT p.Ala2739Thr Uncertain significance ★★ same type
HTT p.Arg1654Trp 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

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-arg2015trp (accessed [today's date]).

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