Is HTT p.Val2617Met (c.7849G>A) pathogenic?

HTT p.Val2617Met (c.7849G>A) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.529); Very rare (popmax 0.00137%, afr); Associated with Huntington disease.

What condition is associated with HTT p.Val2617Met (c.7849G>A)?

HTT p.Val2617Met (c.7849G>A) is associated with Huntington disease (ClinVar).

How common is HTT p.Val2617Met (c.7849G>A) in the general population?

HTT p.Val2617Met (c.7849G>A) is very rare (popmax 0.00137%, 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.Val2617Met (c.7849G>A)?

AlphaMissense predicts ambiguous (score 0.529) — an in-silico prediction, not a clinical call.

HTT p.Val2617Met

c.7849G>A · VCV4278357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Conditions

Huntington disease

Computational evidence

Protein change
AlphaMissense	0.529	ambiguous
REVEL	0.201	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00137% African / African-American · 1/72,946 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000385% 6/1,559,982 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	72,946
European (non-Finnish)	0.000433%	230,824

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.Val2617Met
Coding: c.7849G>A
MANE Select: NM_001045 · reported on NM_001388492
Type: single nucleotide variant
Location: chr4:3228615 (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.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 p.Val2500Ile Uncertain significance ★★ ⚠ same condition
HTT c.7765+10G>A Benign/Likely benign ★★ same condition
HTT p.Val1546= Benign/Likely benign ★★ same condition
HTT c.52CAG[55_59] Likely pathogenic ★ 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-val2617met (accessed [today's date]).

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