CLCN4

Chr XXLD

Cl-/H+ antiporter 4

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

NCBI Gene: 1183ENSG00000073464UniProt: P51793OMIM: 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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
XLDLOEUF 0.151 OMIM phenotype
Clinical Summary— CLCN4
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Gene-Disease Validity (ClinGen)
non-syndromic X-linked intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
57 unique Pathogenic / Likely Pathogenic· 198 VUS of 500 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — CLCN4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.15LOEUF
pLI 0.999
Z-score 4.13
OE 0.00 (0.00–0.15)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
4.52Z-score
OE missense 0.32 (0.27–0.38)
112 obs / 349.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.15)
0≤0.351.4
Missense OE0.32 (0.27–0.38)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 0 / 19.8Missense obs/exp: 112 / 349.7Syn Z: 0.04

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic17
VUS198
Likely Benign109
Benign11
Conflicting4
40
Pathogenic
17
Likely Pathogenic
198
VUS
109
Likely Benign
11
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
1
24
0
40
Likely Pathogenic
5
12
0
0
17
VUS
1
190
4
3
198
Likely Benign
0
3
42
64
109
Benign
0
3
4
4
11
Conflicting
—4
Total212097471379

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CLCN4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients