Is GJB2 p.Ser85Pro (c.253T>C) pathogenic?

GJB2 p.Ser85Pro (c.253T>C) is classified Likely pathogenic in GJB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-03). AlphaMissense: likely pathogenic (0.9839); Very rare (popmax 0.00446%, eas); Associated with autosomal dominant keratitis-ichthyosis-hearing loss syndrome.

What condition is associated with GJB2 p.Ser85Pro (c.253T>C)?

GJB2 p.Ser85Pro (c.253T>C) is associated with autosomal dominant keratitis-ichthyosis-hearing loss syndrome, keratoderma hereditarium mutilans, palmoplantar keratoderma-deafness syndrome (ClinVar).

How common is GJB2 p.Ser85Pro (c.253T>C) in the general population?

GJB2 p.Ser85Pro (c.253T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

How is KID syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GJB2 p.Ser85Pro (c.253T>C)?

AlphaMissense predicts likely pathogenic (score 0.9839) — an in-silico prediction, not a clinical call.

GJB2 p.Ser85Pro

c.253T>C · VCV3575780

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant keratitis-ichthyosis-hearing loss syndrome

Computational evidence

Protein change
AlphaMissense	0.9839	likely pathogenic ✓ concordant with ClinVar
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -13.75	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 9.4	GERP -0.45, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 677 bp · p 0.74 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,044 alleles · very rare exomes 2/1,461,812 · genomes 0/152,232 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GJB2
Protein: p.Ser85Pro
Coding: c.253T>C
MANE Select: NM_004004
Type: single nucleotide variant
Location: chr13:20189329 (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 85: a UniProt-annotated variant site (in dfnb1a); an α-helix

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

Disease context

autosomal dominant keratitis-ichthyosis-hearing loss syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: keratoderma hereditarium mutilans palmoplantar keratoderma-deafness syndrome Bart-Pumphrey syndrome autosomal recessive nonsyndromic hearing loss 1A autosomal dominant nonsyndromic hearing loss 3A ichthyosis, hystrix-like, with hearing loss

For KID syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Neonatal

Similar variants

GJB2 p.Ser85= Likely benign ★ 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
GJB2 p.Met1Arg 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-ser85pro (accessed [today's date]).

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