Is GJB2 p.Pro173Arg (c.518C>G) pathogenic?

GJB2 p.Pro173Arg (c.518C>G) is classified Likely pathogenic in GJB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-02). AlphaMissense: likely pathogenic (0.9874); Absent from gnomAD v4.1.

How common is GJB2 p.Pro173Arg (c.518C>G) in the general population?

GJB2 p.Pro173Arg (c.518C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GJB2 p.Pro173Arg (c.518C>G)?

AlphaMissense predicts likely pathogenic (score 0.9874) — an in-silico prediction, not a clinical call.

GJB2 p.Pro173Arg

c.518C>G · rs1555341843 · VCV2137453

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9874 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9874	likely pathogenic ✓ concordant with ClinVar
REVEL	0.977	strongly pathogenic-leaning
SaProt	LLR -15.95	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 677 bp · p 0.74 · regional, not allelic
Overall
CADD	27.6	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: GJB2
Protein: p.Pro173Arg
Coding: c.518C>G
MANE Select: NM_004004
dbSNP: rs1555341843
Type: single nucleotide variant
Location: chr13:20189064 (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 173: a UniProt-annotated variant site (in dfnb1a)

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

Similar variants

GJB2 p.Pro173Ser Likely pathogenic ★★ same residue
GJB2 p.Pro173Leu 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
GJB2 p.Met195Thr Likely pathogenic ★★★ same type
GJB2 p.Met195Val 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-pro173arg (accessed [today's date]).

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