Is HTT p.Thr1253Met (c.3758C>T) pathogenic?

HTT p.Thr1253Met (c.3758C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: likely benign (0.1935); Ultra-rare (popmax 0.0196%, amr).

How common is HTT p.Thr1253Met (c.3758C>T) in the general population?

HTT p.Thr1253Met (c.3758C>T) is ultra-rare (popmax 0.0196%, amr) (gnomAD).

What do computational predictors say about HTT p.Thr1253Met (c.3758C>T)?

AlphaMissense predicts likely benign (score 0.1935) — an in-silico prediction, not a clinical call.

HTT p.Thr1253Met

c.3758C>T · rs1473464204 · VCV1352525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1935	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0196% Admixed American · 10/50,986 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00809%

Overall 0.00142% 22/1,548,372 alleles · ultra-rare exomes 17/1,396,162 · genomes 5/152,210 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0196%	5,099
Middle Eastern	0.0167%	6,006
Finnishnot grpmax-eligible	0.00834%	11,985
Remaining individualsnot grpmax-eligible	0.00167%	59,984
European (non-Finnish)	0.000437%	228,782

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.Thr1253Met
Coding: c.3758C>T
MANE Select: NM_001388492
dbSNP: rs1473464204
Type: single nucleotide variant
Location: chr4:3160286 (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-thr1253met (accessed [today's date]).

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