Is GJB2 p.Lys188fs (c.564_565del) pathogenic?

GJB2 p.Lys188fs (c.564565del) is classified Conflicting classifications of pathogenicity in GJB2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-15). Ultra-rare (popmax 0.0107%, afr); Associated with Rare genetic deafness.

What condition is associated with GJB2 p.Lys188fs (c.564_565del)?

GJB2 p.Lys188fs (c.564_565del) is associated with Rare genetic deafness, autosomal recessive nonsyndromic hearing loss 1A, autosomal dominant nonsyndromic hearing loss 3A (ClinVar).

How common is GJB2 p.Lys188fs (c.564_565del) in the general population?

GJB2 p.Lys188fs (c.564_565del) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

GJB2 p.Lys188fs

c.564_565del · rs770116143 · VCV371691

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

Rare genetic deafness

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 10	GERP -0.19, phastCons 1
Overall
CADD	34.0	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 0.0107% African / African-American · 8/74,924 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000496% 8/1,613,974 alleles · ultra-rare

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.Lys188fs
Coding: c.564_565del
MANE Select: NM_004004
dbSNP: rs770116143
Type: Deletion
Location: chr13:20189017 (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 188: an α-helix; a UniProt-annotated variant site (in dfnb1a)

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

Disease context

Rare genetic deafness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 1A autosomal dominant nonsyndromic hearing loss 3A

Similar variants

GJB2 p.Lys188Arg Likely pathogenic ★★★ same residue
GJB2 p.Gly12fs Pathogenic ★★★ same condition
GJB2 p.Leu56fs Pathogenic ★★★ same condition
GJB2 p.Leu79fs Pathogenic ★★★ same condition
GJB2 p.Arg216fs Pathogenic/Likely pathogenic ★★ same condition
GJB2 p.Gly11fs Pathogenic ★★ same condition
GJB2 p.Gly4fs Pathogenic/Likely pathogenic ★★ same condition
GJB2 p.Gly59fs 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-lys188fs (accessed [today's date]).

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