Is HTT p.Arg2893Leu (c.8678G>T) pathogenic?

HTT p.Arg2893Leu (c.8678G>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-01). AlphaMissense: likely benign (0.199); Very rare (popmax 0.00667%, amr).

How common is HTT p.Arg2893Leu (c.8678G>T) in the general population?

HTT p.Arg2893Leu (c.8678G>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about HTT p.Arg2893Leu (c.8678G>T)?

AlphaMissense predicts likely benign (score 0.199) — an in-silico prediction, not a clinical call.

HTT p.Arg2893Leu

c.8678G>T · rs574794357 · VCV1350636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Computational evidence

Protein change
AlphaMissense	0.199	likely benign
REVEL	0.382	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,010 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000744% 12/1,613,634 alleles · very rare exomes 5/1,461,310 · genomes 7/152,324 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0064%	15,625
African / African-American	0.00133%	75,050
European (non-Finnish)	0.000254%	393,343

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.Arg2893Leu
Coding: c.8678G>T
MANE Select: NM_001388492
dbSNP: rs574794357
Type: single nucleotide variant
Location: chr4:3235671 (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-arg2893leu (accessed [today's date]).

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