Is GNB2 p.Arg280Ser (c.838C>A) pathogenic?

GNB2 p.Arg280Ser (c.838C>A) is classified Uncertain significance in GNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-19). AlphaMissense: likely pathogenic (0.6848); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia and dysmorphic facies.

What condition is associated with GNB2 p.Arg280Ser (c.838C>A)?

GNB2 p.Arg280Ser (c.838C>A) is associated with neurodevelopmental disorder with hypotonia and dysmorphic facies (ClinVar).

How common is GNB2 p.Arg280Ser (c.838C>A) in the general population?

GNB2 p.Arg280Ser (c.838C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB2 p.Arg280Ser (c.838C>A)?

AlphaMissense predicts likely pathogenic (score 0.6848) — an in-silico prediction, not a clinical call.

GNB2 p.Arg280Ser

c.838C>A · VCV4854467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6848 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hypotonia and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.6848	likely pathogenic
REVEL	0.209	benign-leaning
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 3.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 2,532 bp · p 8.1e-18 · regional, not allelic
Overall
CADD	23.1	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: GNB2
Protein: p.Arg280Ser
Coding: c.838C>A
MANE Select: NM_005273
Type: single nucleotide variant
Location: chr7:100678536 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 96.89 · 1 PDB

Full GNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hypotonia and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNB2 p.Ala73Thr Pathogenic/Likely pathogenic ★★ same condition
GNB2 p.Asn268Ile Likely pathogenic ★ ⚠ same condition
GNB2 p.Asp76Gly Pathogenic ★ same condition
GNB2 p.Gly77Trp Likely pathogenic ★ same condition
GNB2 p.Lys89Glu Pathogenic ★ same condition
GNB2 p.Ile80Asn Uncertain significance ★ ⚠ same condition
GNB2 p.Leu262Phe Uncertain significance ★ ⚠ same condition
GNB2 p.Leu95Pro Conflicting classifications of pathogenicity ★ ⚠ 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/gnb2-p-arg280ser (accessed [today's date]).

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