CLDN9

Chr 16AR

claudin 9

Also known as: DFNB116

NCBI Gene: 9080 ENSG00000213937 UniProt: O95484 OMIM: 615799

This gene encodes claudin-9, an integral membrane protein that forms tight junctions and creates calcium-independent cell adhesion to prevent solutes and water from passing between epithelial cell sheets. Mutations cause autosomal recessive deafness (ARHL 116), specifically affecting sensory cells in the hearing organ. The gene shows low constraint to loss-of-function variation, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. This protein is one of the entry cofactors for hepatitis C virus. Mouse studies revealed that this gene is required for the preservation of sensory cells in the hearing organ and the gene deficiency is associated with deafness. [provided by RefSeq, Jun 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.901 OMIM phenotype

Clinical Summary— CLDN9

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Gene-Disease Validity (ClinGen)

hearing loss, autosomal recessive 116 · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.90LOEUF

pLI 0.000

Z-score -0.65

OE 1.30 (0.71–1.90)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.08Z-score

OE missense 1.26 (1.11–1.42)

179 obs / 142.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.30 (0.71–1.90)

0≤0.351.4

Missense OE?1.26 (1.11–1.42)

0≤0.61.4

Synonymous OE?1.36

0≤1.21.6

LoF obs/exp: 7 / 5.4Missense obs/exp: 179 / 142.6Syn Z: -2.42

This gene — mechanism propensity

0.78top 25%

GOF

0.86top 5%

LOF

0.1993th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.