Is GJB2 p.Pro173Ser (c.517C>T) pathogenic?

GJB2 p.Pro173Ser (c.517C>T) is classified Likely pathogenic in GJB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.9969); Absent from gnomAD v4.1; Associated with autosomal recessive nonsyndromic hearing loss 1A.

What condition is associated with GJB2 p.Pro173Ser (c.517C>T)?

GJB2 p.Pro173Ser (c.517C>T) is associated with autosomal recessive nonsyndromic hearing loss 1A (ClinVar).

How common is GJB2 p.Pro173Ser (c.517C>T) in the general population?

GJB2 p.Pro173Ser (c.517C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GJB2 p.Pro173Ser (c.517C>T)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

GJB2 p.Pro173Ser

c.517C>T · rs1959056736 · VCV842349

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9969 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 1A

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic ✓ concordant with ClinVar · top 4% in GJB2
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -14.88	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	26.6	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.Pro173Ser
Coding: c.517C>T
MANE Select: NM_004004
dbSNP: rs1959056736
Type: single nucleotide variant
Location: chr13:20189065 (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

Disease context

autosomal recessive nonsyndromic hearing loss 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GJB2 p.Pro173Arg Likely pathogenic ★ same residue
GJB2 p.Pro173Leu Uncertain significance ★ ⚠ same residue
GJB2 c.-22-2A>C Likely pathogenic ★★★ same condition
GJB2 p.Gly12Cys Likely pathogenic ★★★ ⚠ same condition
GJB2 p.Leu76Pro Likely pathogenic ★★★ same condition
GJB2 p.Lys188Arg Likely pathogenic ★★★ same condition
GJB2 p.Met195Thr Likely pathogenic ★★★ same condition
GJB2 p.Met195Val 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/gjb2-p-pro173ser (accessed [today's date]).

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