Is HTT p.Val2786Ile (c.8356G>A) pathogenic?

HTT p.Val2786Ile (c.8356G>A) is classified Benign in HTT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0667); Common (popmax 34.6%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about HTT p.Val2786Ile (c.8356G>A)?

AlphaMissense predicts likely benign (score 0.0667) — an in-silico prediction, not a clinical call.

HTT p.Val2786Ile

Q: How common is HTT p.Val2786Ile (c.8356G>A) in the general population?

HTT p.Val2786Ile (c.8356G>A) is common (popmax 34.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8356G>A · rs362272 · VCV1531045

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0667 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 34.6%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0667	likely benign
REVEL	0.069	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 -0.18	GERP -3.8
Overall
CADD	0.06	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 34.6% East Asian · 15,490/44,776 alleles

Filtering AF 34.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 34%

Overall 29.3% 472,453/1,610,054 alleles · common exomes 436,161/1,457,786 · genomes 36,292/152,268 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	43%	2
East Asiangrpmax	34.6%	3
European (non-Finnish)	31%	3
Ashkenazi Jewishnot grpmax-eligible	29%	3
Remaining individualsnot grpmax-eligible	27.8%	4
Admixed American	27.4%	4
Amishnot grpmax-eligible	23.1%	4
South Asian	19.6%	5
Middle Eastern	11.8%	8
African / African-American	5.32%	19

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val2786Ile
Coding: c.8356G>A
MANE Select: NM_001388492
dbSNP: rs362272
Type: single nucleotide variant
Location: chr4:3233253 (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 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
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-val2786ile (accessed [today's date]).

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