GeneBe

CLDN9

protein-coding

claudin 9, the group of Claudins

Gene summary

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]

MANE transcript

NM_020982.4

Inheritance

AR

ClinVar variants

P:3U:61B:13

Top phenotype

Deafness, autosomal recessive 116

gnomAD constraint

pLI —, LoF o/e 1.3

Max pathogenic AF

—

Genomic locus

chr16:3,012,923-3,014,505

External References & Databases

Ensembl (ENSG00000213937)NCBI Gene (9080)OMIM (615799)HGNC:2051GenCCUniProt (O95484)AlphaFoldClinVar (CLDN9)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~1.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessive 116MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033670

Submitter: ClinGen

CLDN9 was first reported in relation to autosomal recessive nonsyndromic hearing loss (DFNB116) in 2019 (Sineni et al., PMID:31175426). 3 variants (c.86delT, p.Leu29ArgfsTer4; c.475G>A, p.Glu159Lys; c.370_372dupATC, p.Ile124dup) that have been reported in 3 probands in 2 publications (PMIDs:31175426, 34265170) are included in this curation. The mechanism of pathogenicity appears to be loss of function, as downregulation of CLDN9 can regulate inner hair cell differentiation (PMID:37873357). This gene-disease relationship is also supported by data showing that CLDN9 is expressed in the outer and the inner hair cells, the supporting cells, the stria vascularis, and in the Reissner’s membrane during embryonic development and in adult mice (PMID:34265170). Additionally, ENU-induced mutant mice with a missense variant in CLDN9 showed no reaction to loud sound bursts and had elevated ABR thresholds compared to wildtype mice (PMID:19696885). A transgenic mouse model also showed that embryonic regulation of CLDN9 levels induces functional ectopic inner hair cells, and that postnatal downregulation of CLDN9 levels coordinates stem cell differentiation into inner hair cells (PMID:37873357). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

hearing loss, autosomal recessive 116LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033670

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 116AR

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31175426Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLDN9 variants in ClinVar

8 Conditions Cataloged
not specifiedTotal: 55
CLDN9-related disorderTotal: 15
not providedTotal: 11
Hearing loss, autosomal recessive 116Total: 7
Nonsyndromic genetic hearing lossTotal: 1
Hearing lossTotal: 1
Pendred syndromeTotal: 1
Hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020982.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
8
clinvar
1
clinvar
 9
missense
1
clinvar
59
clinvar
4
clinvar
 64
nonsense
1
clinvar
 1
start loss
0
frameshift
1
clinvar
1
clinvar
1
clinvar
 3
splice donor/acceptor (+/-2bp)
0
Total126112177

Highest pathogenic variant AF is 0.00024913115

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_020982.4RefSeqNP_066192.11MANE Select
ENST00000445369.3EnsemblENSP00000398017.21MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell adhesion molecules (CAMs) - Homo sapiens (human)
  • Tight junction - Homo sapiens (human)
  • Hepatitis C - Homo sapiens (human)
  • Leukocyte transendothelial migration - Homo sapiens (human)
  • EMT transition in Colorectal Cancer

Biological Process

  • calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules
  • cell-cell junction organization
  • viral entry into host cell

Molecular Function

  • virus receptor activity
  • structural molecule activity
  • protein binding
  • identical protein binding

Cellular Component

  • plasma membrane
  • bicellular tight junction
  • integral component of membrane
  • cell junction
  • intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000445369
Coding exons
1
Length
2050
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.081791431.260.000009281337
Missense (PolyPhen)8764.7781.343662
Synonymous-2.4210073.61.360.00000518522
Loss of Function-0.65475.371.302.33e-749

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium- independent cell-adhesion activity. {ECO:0000250}.;

Intolerance Scores

LoFtool
0.146
RVIS EVS
-0.82
RVIS percentile EVS
11.68

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.286

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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