Is HTT p.Thr1260Met (c.3779C>T) pathogenic?

HTT p.Thr1260Met (c.3779C>T) is classified Benign in HTT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.086); Common (popmax 7.97%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Lopes-Maciel-Rodan syndrome.

What condition is associated with HTT p.Thr1260Met (c.3779C>T)?

HTT p.Thr1260Met (c.3779C>T) is associated with Lopes-Maciel-Rodan syndrome (ClinVar).

What do computational predictors say about HTT p.Thr1260Met (c.3779C>T)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

HTT p.Thr1260Met

Q: How common is HTT p.Thr1260Met (c.3779C>T) in the general population?

HTT p.Thr1260Met (c.3779C>T) is common (popmax 7.97%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3779C>T · rs34315806 · VCV417743

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.97%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Lopes-Maciel-Rodan syndrome

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.106	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.56, phastCons 0.63
Overall
CADD	20.6	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 7.97% African / African-American · 5,840/73,278 alleles

Filtering AF 7.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.73%

Overall 0.472% 7,334/1,552,390 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.97%	13
Middle Eastern	1.02%	98
Admixed American	0.739%	135
Remaining individualsnot grpmax-eligible	0.682%	147
European (non-Finnish)	0.0536%	1,865
South Asian	0.0262%	3,823
Ashkenazi Jewishnot grpmax-eligible	0.0209%	4,776
Finnishnot grpmax-eligible	0.00333%	29,989
East Asian	0.00243%	41,202

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.Thr1260Met
Coding: c.3779C>T
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs34315806
Type: single nucleotide variant
Location: chr4:3160307 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Disease context

Lopes-Maciel-Rodan syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HTT p.Asp920Asn Uncertain significance ★★ same condition
HTT p.Gly2968Asp Uncertain significance ★★ same condition
HTT p.Leu1237Ile Uncertain significance ★★ ⚠ same condition
HTT p.Pro703Leu Uncertain significance ★★ ⚠ same condition
HTT c.7765+10G>A Benign/Likely benign ★★ same condition
HTT p.Val1546= Benign/Likely benign ★★ same condition
HTT p.Leu2307= Likely pathogenic ★ same condition
HTT c.2396-9T>G Uncertain significance ★ same condition

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-thr1260met (accessed [today's date]).

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