Is GJB2 p.Arg98Pro (c.293G>C) pathogenic?

GJB2 p.Arg98Pro (c.293G>C) is classified Uncertain significance in GJB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-24). AlphaMissense: likely pathogenic (0.9751); Absent from gnomAD v4.1.

How common is GJB2 p.Arg98Pro (c.293G>C) in the general population?

GJB2 p.Arg98Pro (c.293G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GJB2 p.Arg98Pro (c.293G>C)?

AlphaMissense predicts likely pathogenic (score 0.9751) — an in-silico prediction, not a clinical call.

GJB2 p.Arg98Pro

c.293G>C · VCV3773926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9751 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9751	likely pathogenic
REVEL	0.673	pathogenic-leaning
SaProt	LLR -13.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -2.9
Regional constraint	o/e 0.98	unconstrained · MANE · 677 bp · p 0.74 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: GJB2
Protein: p.Arg98Pro
Coding: c.293G>C
MANE Select: NM_004004
Type: single nucleotide variant
Location: chr13:20189289 (GRCh38)
Gene constraint: LOEUF 1.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.35 · 24 PDB
Residue 98: a UniProt-annotated variant site (in dfnb1a); an α-helix

Full GJB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GJB2 p.Arg98= Likely benign ★★ same residue
GJB2 p.Arg98Gln Uncertain significance ★ ⚠ same residue
GJB2 p.Arg98Gly Uncertain significance ★ ⚠ same residue
GJB2 p.Arg98Trp Uncertain significance ★ ⚠ same residue
GJB2 c.-22-2A>C Likely pathogenic ★★★ same type
GJB2 p.Gly12Cys Likely pathogenic ★★★ ⚠ same type
GJB2 p.Leu76Pro Likely pathogenic ★★★ same type
GJB2 p.Lys188Arg Likely pathogenic ★★★ same type

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/gjb2-p-arg98pro (accessed [today's date]).

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