Is GNB3 p.Ser84Arg (c.252C>G) pathogenic?

GNB3 p.Ser84Arg (c.252C>G) is classified Uncertain significance in GNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely pathogenic (0.9947); Very rare (popmax 0.000124%); Associated with Inborn genetic diseases.

What condition is associated with GNB3 p.Ser84Arg (c.252C>G)?

GNB3 p.Ser84Arg (c.252C>G) is associated with Inborn genetic diseases (ClinVar).

How common is GNB3 p.Ser84Arg (c.252C>G) in the general population?

GNB3 p.Ser84Arg (c.252C>G) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about GNB3 p.Ser84Arg (c.252C>G)?

AlphaMissense predicts likely pathogenic (score 0.9947) — an in-silico prediction, not a clinical call.

GNB3 p.Ser84Arg

c.252C>G · rs1365631818 · VCV2299861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9947	likely pathogenic
REVEL	0.131	moderately benign-leaning
SaProt	LLR -11.38	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	loss · gain 0.14 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.49	GERP -4.9, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	22.9	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 0.000124%

Overall 0.000124% 2/1,613,902 alleles · very rare exomes 2/1,461,708 · genomes 0/152,194 · joint denominator

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.Ser84Arg
Coding: c.252C>G
MANE Select: NM_002075
dbSNP: rs1365631818
Type: single nucleotide variant
Location: chr12:6843222 (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.Ala106Ser Uncertain significance ★★ ⚠ same condition
GNB3 p.Ala231Thr Uncertain significance ★★ ⚠ same condition
GNB3 p.Ala64Thr Uncertain significance ★★ ⚠ same condition
GNB3 p.Arg129His 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-ser84arg (accessed [today's date]).

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