Is HTT p.His2303= (c.6909C>T) pathogenic?

HTT p.His2303= (c.6909C>T) is classified Likely benign in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-18). Ultra-rare (popmax 0.0189%, afr).

How common is HTT p.His2303= (c.6909C>T) in the general population?

HTT p.His2303= (c.6909C>T) is ultra-rare (popmax 0.0189%, afr) (gnomAD).

HTT p.His2303=

c.6909C>T · rs761834017 · VCV1659141

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0189%, afr)

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 -12	GERP -4.2
Overall
CADD	2.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0189% African / African-American · 14/74,168 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.011%

Overall 0.0115% 184/1,593,624 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0189%	5,298
Remaining individualsnot grpmax-eligible	0.0146%	6,833
European (non-Finnish)	0.0134%	7,439
South Asian	0.00339%	29,497
Finnishnot grpmax-eligible	0.00157%	63,538

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.His2303=
Coding: c.6909C>T
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs761834017
Type: single nucleotide variant
Location: chr4:3214092 (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.His2303Arg 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-his2303 (accessed [today's date]).

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