Is HTT p.His2188Leu (c.6563A>T) pathogenic?

HTT p.His2188Leu (c.6563A>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-07). AlphaMissense: likely benign (0.0965); Ultra-rare (popmax 0.064%, afr).

How common is HTT p.His2188Leu (c.6563A>T) in the general population?

HTT p.His2188Leu (c.6563A>T) is ultra-rare (popmax 0.064%, afr) (gnomAD).

What do computational predictors say about HTT p.His2188Leu (c.6563A>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

HTT p.His2188Leu

c.6563A>T · rs573353052 · VCV1414218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.064%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.052	moderately 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 6.2	GERP 2.1, phastCons 1
Overall
CADD	19.04	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.064% African / African-American · 48/75,056 alleles

Filtering AF 0.0495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.00496% 80/1,614,214 alleles · ultra-rare exomes 51/1,461,878 · genomes 29/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.064%	1,564
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0224%	4,465
Admixed American	0.0117%	8,575
South Asian	0.0022%	45,542
European (non-Finnish)	0.000508%	196,672

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.His2188Leu
Coding: c.6563A>T
MANE Select: NM_001388492
dbSNP: rs573353052
Type: single nucleotide variant
Location: chr4:3212077 (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-his2188leu (accessed [today's date]).

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