Is HTT p.Val2500Ile (c.7498G>A) pathogenic?

HTT p.Val2500Ile (c.7498G>A) is classified Uncertain significance in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-04). AlphaMissense: likely benign (0.0958); Very rare (popmax 0.00268%, afr); Associated with Huntington disease.

What condition is associated with HTT p.Val2500Ile (c.7498G>A)?

HTT p.Val2500Ile (c.7498G>A) is associated with Huntington disease (ClinVar).

How common is HTT p.Val2500Ile (c.7498G>A) in the general population?

HTT p.Val2500Ile (c.7498G>A) is very rare (popmax 0.00268%, afr) (gnomAD).

How is Huntington disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HTT p.Val2500Ile (c.7498G>A)?

AlphaMissense predicts likely benign (score 0.0958) — an in-silico prediction, not a clinical call.

HTT p.Val2500Ile

c.7498G>A · rs371399733 · VCV1355049

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Huntington disease

Computational evidence

Protein change
AlphaMissense	0.0958	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00268% African / African-American · 2/74,612 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00193% 31/1,604,380 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,306
European (non-Finnish)	0.0023%	43,528
South Asian	0.00222%	44,948

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.Val2500Ile
Coding: c.7498G>A
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs371399733
Type: single nucleotide variant
Location: chr4:3223433 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Disease context

Huntington disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Huntington disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-9 / 100 000 (Greece)

Similar variants

HTT p.Val2500= Likely benign ★ same residue
HTT p.Asp920Asn Uncertain significance ★★ same condition
HTT p.Gly2084Arg Uncertain significance ★★ same condition
HTT p.Gly2968Asp Uncertain significance ★★ same condition
HTT p.Pro703Leu Uncertain significance ★★ ⚠ same condition
HTT c.7765+10G>A Benign/Likely benign ★★ same condition
HTT p.Val1546= Benign/Likely benign ★★ same condition
HTT p.Val2617Met Uncertain significance ★ 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-val2500ile (accessed [today's date]).

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