Is HTT p.Ala229Val (c.686C>T) pathogenic?

HTT p.Ala229Val (c.686C>T) is classified Likely benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-02). AlphaMissense: ambiguous (0.3416); Very rare (popmax 8.47e-05%, nfe); Associated with HTT-related disorder.

What condition is associated with HTT p.Ala229Val (c.686C>T)?

HTT p.Ala229Val (c.686C>T) is associated with HTT-related disorder (ClinVar).

How common is HTT p.Ala229Val (c.686C>T) in the general population?

HTT p.Ala229Val (c.686C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HTT p.Ala229Val (c.686C>T)?

AlphaMissense predicts ambiguous (score 0.3416) — an in-silico prediction, not a clinical call.

HTT p.Ala229Val

c.686C>T · rs2475891286 · VCV3048422

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3416 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

HTT-related disorder

Computational evidence

Protein change
AlphaMissense	0.3416	ambiguous
REVEL	0.489	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2, phastCons 1
Overall
CADD	25.7	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 8.47e-05% European (non-Finnish) · 1/1,180,002 alleles

Overall 6.84e-05% 1/1,461,860 alleles · very rare

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.Ala229Val
Coding: c.686C>T
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs2475891286
Type: single nucleotide variant
Location: chr4:3107362 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 229: an α-helix

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

Disease context

HTT-related disorder

Similar variants

HTT p.Phe1142= Likely benign ★★ same condition
HTT p.Pro2946= Likely benign ★★ same condition
HTT p.Val2008= Likely benign ★★ same condition
HTT p.Ala1089= Benign ★ same condition
HTT p.Ala2022= Likely benign ★ same condition
HTT p.Ala2338= Likely benign ★ same condition
HTT p.Ala2644= Benign ★ same condition
HTT p.Ala2945= Likely benign ★ same condition

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-ala229val (accessed [today's date]).

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