Is HTT p.Leu312Pro (c.935T>C) pathogenic?

HTT p.Leu312Pro (c.935T>C) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely pathogenic (0.89); Very rare (popmax 8.47e-05%, nfe).

How common is HTT p.Leu312Pro (c.935T>C) in the general population?

HTT p.Leu312Pro (c.935T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HTT p.Leu312Pro (c.935T>C)?

AlphaMissense predicts likely pathogenic (score 0.89) — an in-silico prediction, not a clinical call.

HTT p.Leu312Pro

c.935T>C · rs2110172445 · VCV1387701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.89 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.89	likely pathogenic
REVEL	0.783	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,179,948 alleles

Overall 6.2e-05% 1/1,613,766 alleles · very rare exomes 1/1,461,376 · genomes 0/152,390 · joint denominator

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.Leu312Pro
Coding: c.935T>C
MANE Select: NM_001388492
dbSNP: rs2110172445
Type: single nucleotide variant
Location: chr4:3116130 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 312: an α-helix

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-leu312pro (accessed [today's date]).

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