Is GJB3 p.Lys115fs (c.342del) pathogenic?

GJB3 p.Lys115fs (c.342del) is classified Uncertain significance in GJB3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-30). Ultra-rare (popmax 0.0187%, sas); Associated with erythrokeratodermia variabilis.

What condition is associated with GJB3 p.Lys115fs (c.342del)?

GJB3 p.Lys115fs (c.342del) is associated with erythrokeratodermia variabilis, autosomal recessive nonsyndromic hearing loss 1A, autosomal dominant nonsyndromic hearing loss 2B (ClinVar).

How common is GJB3 p.Lys115fs (c.342del) in the general population?

GJB3 p.Lys115fs (c.342del) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

How is Erythrokeratodermia variabilis inherited?

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

GJB3 p.Lys115fs

c.342del · rs748575478 · VCV806107

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Conditions

erythrokeratodermia variabilis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.7	GERP -5
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,080 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00427% 69/1,614,046 alleles · ultra-rare exomes 63/1,461,768 · genomes 6/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Remaining individualsnot grpmax-eligible	0.0144%	6,945
European (non-Finnish)	0.00339%	29,500
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,013

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.Lys115fs
Coding: c.342del
MANE Select: NM_024009
dbSNP: rs748575478
Type: Deletion
Location: chr1:34785103 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 1A autosomal dominant nonsyndromic hearing loss 2B erythrokeratodermia variabilis et progressiva 1

For Erythrokeratodermia variabilis (Orphanet):

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

Similar variants

GJB3 p.Leu218_Asp221del Conflicting classifications of pathogenicity ★ same condition
GJB3 p.Lys115Thr Uncertain significance ★ ⚠ same residue
GJB3 p.Ser230fs Uncertain significance ★ same condition
GJB3 p.Ala196Thr Uncertain significance ★★ ⚠ same condition
GJB3 p.Arg180Ter Uncertain significance ★★ same condition
GJB3 p.Arg224Ter Uncertain significance ★★ same condition
GJB3 p.Arg22His Uncertain significance ★★ ⚠ same condition
GJB3 p.Val27Met Uncertain significance ★★ ⚠ 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-lys115fs (accessed [today's date]).

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