Is GJB2 p.Val91fs (c.269dup) pathogenic?

GJB2 p.Val91fs (c.269dup) is classified Pathogenic in GJB2 (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-20). Very rare (popmax 0.00585%, nfe); Associated with Rare genetic deafness.

What condition is associated with GJB2 p.Val91fs (c.269dup)?

GJB2 p.Val91fs (c.269dup) is associated with Rare genetic deafness, keratoderma hereditarium mutilans, autosomal dominant keratitis-ichthyosis-hearing loss syndrome (ClinVar).

How common is GJB2 p.Val91fs (c.269dup) in the general population?

GJB2 p.Val91fs (c.269dup) is very rare (popmax 0.00585%, nfe) (gnomAD).

GJB2 p.Val91fs

c.269dup · rs730880338 · VCV177737

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

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 1.1	GERP -0.14, 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 0.00585% European (non-Finnish) · 69/1,180,032 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00489% 79/1,613,926 alleles · very rare exomes 77/1,461,776 · genomes 2/152,150 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.00585%	17,102
Admixed American	0.00167%	60,002

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val91fs
Coding: c.269dup
MANE Select: NM_004004
dbSNP: rs730880338
Type: Duplication
Location: chr13:20189312 (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 91: 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

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

Also linked: keratoderma hereditarium mutilans autosomal dominant keratitis-ichthyosis-hearing loss syndrome 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 nonsyndromic genetic hearing loss GJB2-related disorder

Similar variants

GJB2 p.Ala171fs Pathogenic ★★ same condition
GJB2 p.Ala78fs Pathogenic/Likely pathogenic ★★ same condition
GJB2 p.Asn14fs Pathogenic/Likely pathogenic ★★ same condition
GJB2 p.Cys202Ter Pathogenic/Likely pathogenic ★★ same condition
GJB2 p.Tyr97Ter Pathogenic ★★ same condition
GJB2 p.Val13fs Pathogenic/Likely pathogenic ★★ same condition
GJB2 p.Ala96fs Likely pathogenic ★ same condition
GJB2 p.Arg165fs Likely 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-val91fs (accessed [today's date]).

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