CLCN5

Chr XXLR

Cl-/H+ antiporter 5

Also known as: CLC5, CLCK2, ClC-5, DENT1, DENTS, NPHL1, NPHL2, XLRH

NCBI Gene: 1184ENSG00000171365UniProt: P51795OMIM: 300008

This gene encodes a proton-coupled chloride transporter that functions in endosomal acidification and facilitates albumin uptake in renal proximal tubules. Mutations cause X-linked recessive Dent disease 1, characterized by low molecular weight proteinuria, hypercalciuric nephrocalcinosis, nephrolithiasis, and hypophosphatemic rickets. The gene is highly constrained against loss-of-function variants (pLI 0.99), reflecting its essential role in renal tubular function.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
XLRLOEUF 0.284 OMIM phenotypes
Clinical Summary— CLCN5
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Gene-Disease Validity (ClinGen)
Dent disease type 1 · 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 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
156 unique Pathogenic / Likely Pathogenic· 213 VUS of 600 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — CLCN5
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.28LOEUF
pLI 0.992
Z-score 4.36
OE 0.11 (0.05–0.28)
Highly constrained

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

Missense Constraint
2.53Z-score
OE missense 0.60 (0.54–0.68)
195 obs / 323.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.11 (0.05–0.28)
0≤0.351.4
Missense OE0.60 (0.54–0.68)
0≤0.61.4
Synonymous OE0.81
0≤1.21.6
LoF obs/exp: 3 / 27.8Missense obs/exp: 195 / 323.2Syn Z: 1.59

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic98
Likely Pathogenic58
VUS213
Likely Benign93
Benign31
Conflicting21
98
Pathogenic
58
Likely Pathogenic
213
VUS
93
Likely Benign
31
Benign
21
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
36
5
57
0
98
Likely Pathogenic
41
14
2
1
58
VUS
1
165
43
4
213
Likely Benign
0
7
35
51
93
Benign
0
1
24
6
31
Conflicting
—21
Total7819216162514

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

View in ClinVar →

Protein Context — Lollipop Plot

CLCN5 · 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
Update on Dent Disease.
Ehlayel AM et al.·Pediatr Clin North Am
2019Review
Uncovering genetic causes of hypophosphatemia.
Puente-Ruiz N et al.·J Intern Med
2023Review
Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1.
Mansour-Hendili L et al.·Hum Mutat
2015Review
Molecular Pathophysiology of Acid-Base Disorders.
Wagner CA et al.·Semin Nephrol
2019Review
Clinical and Molecular Genetic Characteristics of Patients with Hereditary Hypophosphatemia.
Eltan M et al.·J Clin Endocrinol Metab
2025Cohort
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Database of CLCN5 Pathogenic Variants Causing Dent Disease.
Lyu P et al.·Kidney Int Rep
2026Open Access
Molecular Mechanisms of CLCN5 Missense Mutations in Dent Disease Type 1: A Comprehensive Computational Analysis and Clinical Correlations in a Chinese Cohort.
Wu C et al.·J Cell Mol Med
2026Open AccessCohort
CLCN5 inhibits tumorigenesis and fatty acid accumulation in clear cell renal cell carcinoma by regulating Enoyl CoA hydratase and 3-Hydroxyacyl CoA dehydrogenase.
Yu T et al.·Int J Med Sci
2025Open Access
Bioinformatics analysis of a CLCN5 geneframeshift mutation in a patient with Dent disease.
Zhang Y et al.·Zhong Nan Da Xue Xue Bao Yi Xue Ban
2025Open Access
[Clinical and genetic analysis of a patient with Dent disease due to hemizygous variant of the CLCN5 gene].
Liu F et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2025
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