Is GNB3 p.Ala248Ser (c.742G>T) pathogenic?

GNB3 p.Ala248Ser (c.742G>T) is classified Uncertain significance in GNB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.2656); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with GNB3 p.Ala248Ser (c.742G>T)?

GNB3 p.Ala248Ser (c.742G>T) is associated with Inborn genetic diseases (ClinVar).

How common is GNB3 p.Ala248Ser (c.742G>T) in the general population?

GNB3 p.Ala248Ser (c.742G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about GNB3 p.Ala248Ser (c.742G>T)?

AlphaMissense predicts likely benign (score 0.2656) — an in-silico prediction, not a clinical call.

GNB3 p.Ala248Ser

c.742G>T · rs372895359 · VCV1467519

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2656	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,026 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000205% 3/1,461,032 alleles · very rare

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.Ala248Ser
Coding: c.742G>T
MANE Select: NM_031299 · reported on NM_002075
dbSNP: rs372895359
Type: single nucleotide variant
Location: chr12:6845628 (GRCh38)

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

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-ala248ser (accessed [today's date]).

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