Is HTT p.Leu1043Val (c.3127T>G) pathogenic?

HTT p.Leu1043Val (c.3127T>G) is classified Likely benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-29). AlphaMissense: likely benign (0.075); Ultra-rare (popmax 0.015%, nfe).

How common is HTT p.Leu1043Val (c.3127T>G) in the general population?

HTT p.Leu1043Val (c.3127T>G) is ultra-rare (popmax 0.015%, nfe) (gnomAD).

What do computational predictors say about HTT p.Leu1043Val (c.3127T>G)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

HTT p.Leu1043Val

c.3127T>G · VCV4966157

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.243	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -3.2
Overall
CADD	7.727	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 0.015% European (non-Finnish) · 177/1,178,408 alleles

Filtering AF 0.0132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0123% 199/1,612,300 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0224%	4,461
European (non-Finnish)grpmax	0.015%	6,658
Admixed American	0.00833%	12,000
African / African-American	0.00401%	24,960

Remaining individuals 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.Leu1043Val
Coding: c.3127T>G
MANE Select: NM_001045 · reported on NM_001388492
Type: single nucleotide variant
Location: chr4:3145212 (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 p.Leu1043Ser Uncertain significance ★★ ⚠ 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-leu1043val (accessed [today's date]).

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