Is GNB3 p.Arg219His (c.656G>A) pathogenic?

GNB3 p.Arg219His (c.656G>A) is classified Uncertain significance in GNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-21). AlphaMissense: likely benign (0.2981); Very rare (popmax 0.00769%, sas).

How common is GNB3 p.Arg219His (c.656G>A) in the general population?

GNB3 p.Arg219His (c.656G>A) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about GNB3 p.Arg219His (c.656G>A)?

AlphaMissense predicts likely benign (score 0.2981) — an in-silico prediction, not a clinical call.

GNB3 p.Arg219His

c.656G>A · rs782505727 · VCV1418031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2981	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -12.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,062 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00211% 34/1,613,840 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,009
East Asian	0.00669%	14,958
Remaining individualsnot grpmax-eligible	0.0032%	31,250
European (non-Finnish)	0.0017%	58,994
Finnishnot grpmax-eligible	0.00156%	63,990
African / African-American	0.00133%	74,966

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: GNB3
Protein: p.Arg219His
Coding: c.656G>A
MANE Select: NM_002075
dbSNP: rs782505727
Type: single nucleotide variant
Location: chr12:6843935 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 2 PDB

Full GNB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GNB3 p.Arg219= Benign ★★ same residue
GNB3 p.Arg219Cys Uncertain significance ★ ⚠ same residue
GNB3 c.203+6G>A Uncertain significance ★★ same type
GNB3 p.Ala106Ser Uncertain significance ★★ ⚠ same type
GNB3 p.Ala231Thr Uncertain significance ★★ ⚠ same type
GNB3 p.Ala64Thr Uncertain significance ★★ ⚠ same type
GNB3 p.Arg129His Uncertain significance ★★ ⚠ same type
GNB3 p.Arg137Gln 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/gnb3-p-arg219his (accessed [today's date]).

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