CLCN5

Chr XXLR

Cl-/H+ antiporter 5

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

NCBI Gene: 1184 ENSG00000171365 UniProt: P51795 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

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

142 unique Pathogenic / Likely Pathogenic· 252 VUS of 647 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — CLCN5

Authoritative clinical overview · Recommended first read

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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 OE?0.11 (0.05–0.28)

0≤0.351.4

Missense OE?0.60 (0.54–0.68)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 3 / 27.8Missense obs/exp: 195 / 323.2Syn Z: 1.59

ClinVar Variant Classifications

647 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic75

Likely Pathogenic67

VUS252

Likely Benign100

Benign36

Conflicting25

Pathogenic

Likely Pathogenic

252

VUS

100

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	55	15	5	0	75
Likely Pathogenic	48	18	0	1	67
VUS	2	180	66	4	252
Likely Benign	0	9	37	54	100
Benign	0	2	26	8	36
Conflicting	—				25
Total	105	224	134	67	555

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

View in ClinVar →

77 pathogenic / likely-pathogenic (of 86) ClinVar copy-number / structural variants overlap CLCN5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →