Is GJB3 p.Pro159= (c.477G>A) pathogenic?

GJB3 p.Pro159= (c.477G>A) is classified Benign in GJB3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). Common (popmax 9.05%, afr) — too common for a highly-penetrant pathogenic allele; Associated with erythrokeratodermia variabilis et progressiva 1.

What condition is associated with GJB3 p.Pro159= (c.477G>A)?

GJB3 p.Pro159= (c.477G>A) is associated with erythrokeratodermia variabilis et progressiva 1 (ClinVar).

How is Erythrokeratodermia variabilis inherited?

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

GJB3 p.Pro159=

Q: How common is GJB3 p.Pro159= (c.477G>A) in the general population?

GJB3 p.Pro159= (c.477G>A) is common (popmax 9.05%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.477G>A · rs61732640 · VCV163530

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 9.05%, afr) — too common for a highly-penetrant pathogenic allele

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 -14	GERP -4.7
Overall
CADD	0.032	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.05% African / African-American · 6,784/74,954 alleles

Filtering AF 8.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.8%

Overall 0.539% 8,704/1,613,878 alleles · common exomes 4,758/1,461,734 · genomes 3,946/152,144 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.05%	11
Ashkenazi Jewishnot grpmax-eligible	1.81%	55
Remaining individualsnot grpmax-eligible	0.878%	114
Admixed American	0.63%	159
Middle Eastern	0.511%	196
South Asian	0.0889%	1,124
European (non-Finnish)	0.0291%	3,440
East Asian	0.00223%	44,866

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.Pro159=
Coding: c.477G>A
MANE Select: NM_024009
dbSNP: rs61732640
Type: single nucleotide variant
Location: chr1:34785239 (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.Pro159Leu Uncertain significance ★★ ⚠ same residue
GJB3 p.Pro159Thr 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

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-pro159 (accessed [today's date]).

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