Is HTT p.Asp1082His (c.3244G>C) pathogenic?

HTT p.Asp1082His (c.3244G>C) is classified Conflicting classifications of pathogenicity in HTT (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.9311); Rare (popmax 0.208%, nfe).

How common is HTT p.Asp1082His (c.3244G>C) in the general population?

HTT p.Asp1082His (c.3244G>C) is rare (popmax 0.208%, nfe) (gnomAD).

What do computational predictors say about HTT p.Asp1082His (c.3244G>C)?

AlphaMissense predicts likely pathogenic (score 0.9311) — an in-silico prediction, not a clinical call.

HTT p.Asp1082His

c.3244G>C · rs1065746 · VCV1206059

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9311 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.208%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.9311	likely pathogenic
REVEL	0.693	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Overall
CADD	26.7	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 0.208% European (non-Finnish) · 2,459/1,180,020 alleles

Filtering AF 0.202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.199%

Overall 0.169% 2,735/1,614,136 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.214%	467
European (non-Finnish)grpmax	0.208%	480
Remaining individualsnot grpmax-eligible	0.138%	727
Admixed American	0.0583%	1,715
Middle Eastern	0.033%	3,031
African / African-American	0.0187%	5,361
South Asian	0.0022%	45,539

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.Asp1082His
Coding: c.3244G>C
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs1065746
Type: single nucleotide variant
Location: chr4:3146897 (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-asp1082his (accessed [today's date]).

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