Is GNB3 p.Arg129His (c.386G>A) pathogenic?

GNB3 p.Arg129His (c.386G>A) is classified Uncertain significance in GNB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-25). AlphaMissense: ambiguous (0.4893); Ultra-rare (popmax 0.02%, eas); Associated with Inborn genetic diseases.

What condition is associated with GNB3 p.Arg129His (c.386G>A)?

GNB3 p.Arg129His (c.386G>A) is associated with Inborn genetic diseases (ClinVar).

How common is GNB3 p.Arg129His (c.386G>A) in the general population?

GNB3 p.Arg129His (c.386G>A) is ultra-rare (popmax 0.02%, eas) (gnomAD).

What do computational predictors say about GNB3 p.Arg129His (c.386G>A)?

AlphaMissense predicts ambiguous (score 0.4893) — an in-silico prediction, not a clinical call.

GNB3 p.Arg129His

c.386G>A · rs201797921 · VCV1346519

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4893 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4893	ambiguous
REVEL	0.149	moderately benign-leaning
SaProt	LLR -11.60	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	25.2	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 0.02% East Asian · 9/44,898 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00725% 117/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.02%	4,989
European (non-Finnish)	0.00831%	12,041
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed American	0.005%	20,002
African / African-American	0.00267%	37,460
South Asian	0.0011%	91,088

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.Arg129His
Coding: c.386G>A
MANE Select: NM_002075
dbSNP: rs201797921
Type: single nucleotide variant
Location: chr12:6843481 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNB3 p.Arg129Cys Uncertain significance ★ ⚠ same residue
GNB3 p.Ala106Ser Uncertain significance ★★ ⚠ same condition
GNB3 p.Ala231Thr Uncertain significance ★★ ⚠ same condition
GNB3 p.Ala64Thr Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg150Cys Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg8His Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg96His Uncertain significance ★★ ⚠ same condition
GNB3 p.Asn125Asp Uncertain significance ★★ ⚠ same condition

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-arg129his (accessed [today's date]).

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