Is HTT p.His1547= (c.4641C>T) pathogenic?

HTT p.His1547= (c.4641C>T) is classified Likely benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-14). Ultra-rare (popmax 0.01%, amr).

How common is HTT p.His1547= (c.4641C>T) in the general population?

HTT p.His1547= (c.4641C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

HTT p.His1547=

c.4641C>T · rs774235259 · VCV1542016

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

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 -9.6	GERP -4.5
Overall
CADD	0.543	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,724 alleles

Filtering AF 0.0043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000959% 14/1,459,566 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,954
Remaining individualsnot grpmax-eligible	0.0032%	31,204
East Asian	0.00224%	44,694
European (non-Finnish)	0.000424%	235,786

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.His1547=
Coding: c.4641C>T
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs774235259
Type: single nucleotide variant
Location: chr4:3180543 (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 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-his1547 (accessed [today's date]).

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