Is HTT p.Thr386Met (c.1157C>T) pathogenic?

HTT p.Thr386Met (c.1157C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely benign (0.1091); Very rare (popmax 0.00223%, eas).

How common is HTT p.Thr386Met (c.1157C>T) in the general population?

HTT p.Thr386Met (c.1157C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HTT p.Thr386Met (c.1157C>T)?

AlphaMissense predicts likely benign (score 0.1091) — an in-silico prediction, not a clinical call.

HTT p.Thr386Met

c.1157C>T · rs751024193 · VCV1406094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
AlphaMissense	0.1091	likely benign
REVEL	0.299	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Overall
CADD	26.0	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 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,938 alleles · very rare exomes 11/1,461,770 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
South Asian	0.0022%	45,541
European (non-Finnish)	0.000763%	131,103

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.Thr386Met
Coding: c.1157C>T
MANE Select: NM_001388492
dbSNP: rs751024193
Type: single nucleotide variant
Location: chr4:3121316 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 386: an α-helix

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

Similar variants

HTT p.Thr386= Likely benign ★ same residue
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

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-thr386met (accessed [today's date]).

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