Is HTT p.Leu295= (c.885C>G) pathogenic?

HTT p.Leu295= (c.885C>G) is classified Benign in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). Common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele.

HTT p.Leu295=

Q: How common is HTT p.Leu295= (c.885C>G) in the general population?

HTT p.Leu295= (c.885C>G) is common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.885C>G · rs1936032 · VCV1588738

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.36	GERP -1.4
Overall
CADD	6.547	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.3% African / African-American · 7,722/74,948 alleles

Filtering AF 10.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 10%

Overall 3.15% 50,798/1,612,244 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.3%	10
Middle Eastern	6.29%	16
Amishnot grpmax-eligible	5.93%	17
Remaining individualsnot grpmax-eligible	3.23%	31
European (non-Finnish)	3.1%	32
Finnishnot grpmax-eligible	2.56%	39
Admixed American	2.47%	41
Ashkenazi Jewishnot grpmax-eligible	1.4%	71
South Asian	0.645%	155
East Asian	0.0111%	8,976

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.Leu295=
Coding: c.885C>G
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs1936032
Type: single nucleotide variant
Location: chr4:3115441 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 295: 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-leu295 (accessed [today's date]).

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