Is HTT p.Arg2014Cys (c.6040C>T) pathogenic?

HTT p.Arg2014Cys (c.6040C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-16). AlphaMissense: ambiguous (0.437); Ultra-rare (popmax 0.0218%, amr).

How common is HTT p.Arg2014Cys (c.6040C>T) in the general population?

HTT p.Arg2014Cys (c.6040C>T) is ultra-rare (popmax 0.0218%, amr) (gnomAD).

What do computational predictors say about HTT p.Arg2014Cys (c.6040C>T)?

AlphaMissense predicts ambiguous (score 0.437) — an in-silico prediction, not a clinical call.

HTT p.Arg2014Cys

c.6040C>T · rs566885635 · VCV1385406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, amr)

Computational evidence

Protein change
AlphaMissense	0.437	ambiguous
REVEL	0.361	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	32.0	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 0.0218% Admixed American · 13/59,742 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00118% 19/1,613,070 alleles · ultra-rare exomes 17/1,460,854 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0218%	4,596
East Asian	0.00446%	22,435
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
South Asian	0.0011%	90,836
European (non-Finnish)	0.00017%	589,835

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.Arg2014Cys
Coding: c.6040C>T
MANE Select: NM_001388492
dbSNP: rs566885635
Type: single nucleotide variant
Location: chr4:3206948 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Similar variants

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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
HTT p.Gly2084Arg 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-arg2014cys (accessed [today's date]).

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