Is GNB1 p.Pro94Arg (c.281C>G) pathogenic?

GNB1 p.Pro94Arg (c.281C>G) is classified Conflicting classifications of pathogenicity in GNB1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-10-31). AlphaMissense: likely pathogenic (0.9961); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 42.

What condition is associated with GNB1 p.Pro94Arg (c.281C>G)?

GNB1 p.Pro94Arg (c.281C>G) is associated with intellectual disability, autosomal dominant 42 (ClinVar).

How common is GNB1 p.Pro94Arg (c.281C>G) in the general population?

GNB1 p.Pro94Arg (c.281C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB1 p.Pro94Arg (c.281C>G)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

GNB1 p.Pro94Arg

c.281C>G · rs2522751007 · VCV2000177

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 42

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic
REVEL	0.278	benign-leaning
SaProt	LLR -15.62	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 29 kb · p 7e-38 · regional, not allelic
Overall
CADD	28.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GNB1
Protein: p.Pro94Arg
Coding: c.281C>G
MANE Select: NM_002074
dbSNP: rs2522751007
Type: single nucleotide variant
Location: chr1:1804568 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 97.04 · 1043 PDB
Residue 94: a UniProt-annotated variant site (in mrd42; decreases receptor-driven g protein activation; decreases trimer formation with alpha and gamma subunit; no effect on protein abundance;no effect on complex formation with gamma subunit); a β-strand

Full GNB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 42 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNB1 p.Pro94Ser Uncertain significance ★★ ⚠ same residue
GNB1 p.Pro94Leu Uncertain significance ★ ⚠ same residue
GNB1 c.498-2A>G Likely pathogenic ★★ same condition
GNB1 p.Ala73Ser Pathogenic/Likely pathogenic ★★ same condition
GNB1 p.Ala73Thr Pathogenic/Likely pathogenic ★★ same condition
GNB1 p.Ala92Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
GNB1 p.Asp118Gly Pathogenic ★★ same condition
GNB1 p.Asp118His Likely pathogenic ★★ 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/gnb1-p-pro94arg (accessed [today's date]).

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