Is HTT p.Met2033Val (c.6097A>G) pathogenic?

HTT p.Met2033Val (c.6097A>G) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely benign (0.046); Ultra-rare (popmax 0.0493%, mid).

How common is HTT p.Met2033Val (c.6097A>G) in the general population?

HTT p.Met2033Val (c.6097A>G) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about HTT p.Met2033Val (c.6097A>G)?

AlphaMissense predicts likely benign (score 0.046) — an in-silico prediction, not a clinical call.

HTT p.Met2033Val

c.6097A>G · rs763357755 · VCV1482152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.046 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Computational evidence

Protein change
AlphaMissense	0.046	likely benign
REVEL	0.372	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3.6, phastCons 0.001
Overall
CADD	2.5	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00359% 58/1,613,818 alleles · ultra-rare exomes 39/1,461,608 · genomes 19/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
African / African-American	0.036%	2,775
Admixed American	0.005%	19,995
Remaining individualsnot grpmax-eligible	0.0032%	31,236
East Asian	0.00223%	44,882
European (non-Finnish)	0.00186%	53,633

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.Met2033Val
Coding: c.6097A>G
MANE Select: NM_001388492
dbSNP: rs763357755
Type: single nucleotide variant
Location: chr4:3207302 (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-met2033val (accessed [today's date]).

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