Is HTT p.Gly893Arg (c.2677G>A) pathogenic?

HTT p.Gly893Arg (c.2677G>A) is classified Benign in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.3693); Common (popmax 6.16%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about HTT p.Gly893Arg (c.2677G>A)?

AlphaMissense predicts ambiguous (score 0.3693) — an in-silico prediction, not a clinical call.

HTT p.Gly893Arg

Q: How common is HTT p.Gly893Arg (c.2677G>A) in the general population?

HTT p.Gly893Arg (c.2677G>A) is common (popmax 6.16%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2677G>A · rs363075 · VCV1615277

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3693 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.16%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
AlphaMissense	0.3693	ambiguous
REVEL	0.3	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 1, phastCons 1
Overall
CADD	25.9	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 6.16% European (non-Finnish) · 72,467/1,175,902 alleles

Filtering AF 6.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.11%

Overall 5.26% 84,273/1,603,158 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	6.16%	16
Middle Eastern	5.07%	20
Remaining individualsnot grpmax-eligible	4.97%	20
Amishnot grpmax-eligible	4.39%	23
Admixed American	4.14%	24
Finnishnot grpmax-eligible	4.09%	24
Ashkenazi Jewishnot grpmax-eligible	3.11%	32
South Asian	1.94%	52
African / African-American	1.01%	99
East Asian	0.0112%	8,897

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.Gly893Arg
Coding: c.2677G>A
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs363075
Type: single nucleotide variant
Location: chr4:3135947 (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-gly893arg (accessed [today's date]).

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