CLCN4

Chr XXLD

Cl-/H+ antiporter 4

Also known as: CLC4, ClC-4, ClC-4A, MRX15, MRX49, MRXSRC

NCBI Gene: 1183 ENSG00000073464 UniProt: P51793 OMIM: 302910

The CLCN4 protein is a voltage-dependent chloride channel localized to early endosome membranes. Mutations cause Raynaud-Claes syndrome, an X-linked dominant neurological disorder. The high pLI score (0.999) and low LOEUF score (0.151) indicate the gene is highly intolerant to loss-of-function mutations, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders. Alternate splicing results in two transcript variants that encode different proteins. [provided by RefSeq, Mar 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Raynaud-Claes syndromeMIM #300114

XLD

Clinical highlights

Gene-disease validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.15

LOEUF· LoF intol.

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Mechanism

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GeneReview available — CLCN4