Is GJB3 p.Phe83= (c.249C>T) pathogenic?

GJB3 p.Phe83= (c.249C>T) is classified Uncertain significance in GJB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-28). Very rare (popmax 0.00267%, afr); Associated with erythrokeratodermia variabilis et progressiva 1.

What condition is associated with GJB3 p.Phe83= (c.249C>T)?

GJB3 p.Phe83= (c.249C>T) is associated with erythrokeratodermia variabilis et progressiva 1 (ClinVar).

How common is GJB3 p.Phe83= (c.249C>T) in the general population?

GJB3 p.Phe83= (c.249C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Erythrokeratodermia variabilis inherited?

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

GJB3 p.Phe83=

c.249C>T · rs1640079217 · VCV876776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

erythrokeratodermia variabilis et progressiva 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -5
Overall
CADD	4.967	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,936 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,614,078 alleles · very rare exomes 0/1,461,880 · genomes 2/152,198 · 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: GJB3
Protein: p.Phe83=
Coding: c.249C>T
MANE Select: NM_024009
dbSNP: rs1640079217
Type: single nucleotide variant
Location: chr1:34785011 (GRCh38)
Gene constraint: LOEUF 1.277 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.29

Full GJB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

erythrokeratodermia variabilis et progressiva 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Erythrokeratodermia variabilis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GJB3 p.Phe83Leu Uncertain significance ★ ⚠ same residue
GJB3 p.Arg224Ter Uncertain significance ★★ same condition
GJB3 p.Arg22His Uncertain significance ★★ ⚠ same condition
GJB3 p.Val27Met Uncertain significance ★★ ⚠ same condition
GJB3 c.-141C>G Benign ★★ same condition
GJB3 c.*218C>A Benign ★★ same condition
GJB3 c.*231G>A Likely benign ★★ same condition
GJB3 c.*369G>C Benign ★★ 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/gjb3-p-phe83 (accessed [today's date]).

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