CLCN5

Summary

CLCN5 (Cl-/H+ antiporter 5, HGNC:2023) is a protein-coding gene on chromosome Xp11.23, encoding H(+)/Cl(-) exchange transporter 5 (P51795). Proton-coupled chloride transporter. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 1184 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Dent disease type 1 (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 653 total — 81 pathogenic, 60 likely-pathogenic
• Phenotypes (HPO): 40
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001127898

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2023
Approved symbol	CLCN5
Name	Cl-/H+ antiporter 5
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	DENTS, XLRH, hClC-K2, hCIC-K2, CLC5, XRN, ClC-5
Ensembl gene	ENSG00000171365
Ensembl biotype	protein_coding
OMIM	300008
Entrez	1184

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 nonsense_mediated_decay

ENST00000307367, ENST00000376088, ENST00000376091, ENST00000376108, ENST00000482218, ENST00000642383, ENST00000642885, ENST00000643129, ENST00000646398, ENST00000854414

RefSeq mRNA: 5 — MANE Select: NM_001127898 NM_000084, NM_001127898, NM_001127899, NM_001272102, NM_001282163

CCDS: CCDS14328, CCDS48115, CCDS69763

Canonical transcript exons

ENST00000376091 — 15 exons

Exon	Start	End
ENSE00001149502	50090670	50090886
ENSE00001149510	50090116	50090514
ENSE00001149517	50088698	50088884
ENSE00001149530	50086328	50086870
ENSE00001149540	50085980	50086060
ENSE00001149548	50081641	50081847
ENSE00001149559	50080594	50080716
ENSE00001149569	50075795	50075982
ENSE00001149580	50072489	50072588
ENSE00001469352	49923407	49923482
ENSE00001615142	50042316	50042462
ENSE00001853889	49922596	49922792
ENSE00001953341	50092129	50099230
ENSE00003521115	50069879	50070030
ENSE00003706450	49925171	49925314

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 96.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.6516 / max 250.1585, expressed in 1718 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196339	3.4438	1440
196340	2.0671	1012
196338	1.7152	955
196341	1.2032	410
196349	0.7041	254
196348	0.2804	141
196342	0.1734	80
196350	0.0643	29

Top tissues by expression

276 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	96.40	gold quality
secondary oocyte	CL:0000655	95.26	gold quality
corpus epididymis	UBERON:0004359	91.41	gold quality
adult mammalian kidney	UBERON:0000082	86.94	gold quality
kidney	UBERON:0002113	86.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.42	gold quality
oocyte	CL:0000023	82.55	gold quality
cartilage tissue	UBERON:0002418	82.27	gold quality
pigmented layer of retina	UBERON:0001782	81.99	gold quality
retina	UBERON:0000966	81.97	gold quality
jejunal mucosa	UBERON:0000399	81.42	gold quality
liver	UBERON:0002107	81.40	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.66	gold quality
germinal epithelium of ovary	UBERON:0001304	80.42	silver quality
metanephros cortex	UBERON:0010533	80.27	gold quality
adult organism	UBERON:0007023	79.92	gold quality
right lobe of liver	UBERON:0001114	79.70	gold quality
cortex of kidney	UBERON:0001225	79.57	gold quality
caput epididymis	UBERON:0004358	77.96	gold quality
adrenal tissue	UBERON:0018303	76.94	gold quality
cauda epididymis	UBERON:0004360	76.88	gold quality
left ovary	UBERON:0002119	76.72	gold quality
ovary	UBERON:0000992	76.61	gold quality
upper leg skin	UBERON:0004262	76.55	gold quality
metanephros	UBERON:0000081	76.47	gold quality
tibialis anterior	UBERON:0001385	76.38	silver quality
pancreatic ductal cell	CL:0002079	76.15	gold quality
kidney epithelium	UBERON:0004819	76.01	silver quality
monocyte	CL:0000576	75.62	gold quality
right ovary	UBERON:0002118	75.25	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	67.07
E-HCAD-10	yes	12.17
E-ANND-3	yes	7.36
E-CURD-135	no	1554.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1A, TFAP4

miRNA regulators (miRDB)

282 targeting CLCN5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• ClC-5 mutations are associated with modifications in the polarity and expression of H+-ATPase, but not ultrastructural alterations in kidney proximal tubule cells (PMID:12631345)
• crucial role for the interaction between the two subunits at the interface of the homodimeric hCLC-5. (PMID:12631358)
• CLCN5 gene mutation in spanish patients with Dent’s disease is associated with this renal tubulopathy. (PMID:12637640)
• Dent’s disease phenotype may be explained by mutations that affect so far unknown regulating elements of the CLCN5 gene or another gene(s), probably encoding CLC-5 accessory protein(s) (PMID:12886045)
• interaction between the C-terminal tail of ClC-5 and cofilin, an actin-associated protein that is crucial in the regulation of albumin uptake by the proximal tubule (PMID:12904289)
• ClC-5 channel activity can be restored for specific Dent’s mutations by expression of the missing portion of the ClC-5 molecule. (PMID:13679301)
• the first report of a retrotransposon insertion in the CLCN5 gene associated with Dent’s disease (PMID:14569459)
• The segmental expression of ClC-5 and H+-ATPase is essentially achieved during early nephrogenesis, in parallel with the onset of glomerular filtration (PMID:14675051)
• mutation analysis of the coding region of CLCN5 by DNA sequencing in X-linked nephrolithiasis (PMID:15086899)
• Genetic analysis that confirmed the diagnosis pf Dent’s disease and revealed a novel mutation in the CLCN5 gene. (PMID:15571186)
• We conclude that overexpression of ClC-5, specifically amino acids 347-647, can alter the normal translation or trafficking of ENaC and other ion transport proteins by a mechanism that is independent of the chloride conductance of ClC-5. (PMID:15702377)
• first report to characterize mutations in the CLCN5 gene in Korean patients with Dent’s disease; a novel mutation, E609X was reported (PMID:15719255)
• coupled Cl-/H+ transport of ClC-4 and ClC-5 is of significant magnitude in vivo (PMID:16034421)
• both nucleotides induce an increase in thermal stability of ClC-5 Ct, supporting the suggestion that both nucleotides interact with and modify the biophysical properties of this prot (PMID:16686597)
• CLCN5 mutation should be considered irrespective of the presence of hypercalciuria in a patient with low molecular weight proteinuria. (PMID:16807762)
• Dent’s disease is an inherited tubulopathy caused by CLCN5 gene mutations. (PMID:16822791)
• Study reports the structures of the cytoplasmic domain of the human transporter ClC-5 in complex with ATP and ADP; the nucleotides bind to a specific site in the protein. (PMID:17195847)
• Missense mutation W547G can also alter the expression levels of a CLCN5 mRNA splicing variant. (PMID:17262170)
• abnormalities in the CLCN5 and OCRL1 genes in Dent’s disease [review] (PMID:18019214)
• A novel G333R CLCN5 mutation caused defective expression of megalin, cubilin, and Dab2 in a patient with Dent’s disease (PMID:18025833)
• CLCN5 mutation in Dent’s disease (PMID:18184518)
• CAIII expression is upregulated in kidney cortex samples from the end-stage kidney of a patient with Dent’s disease owing to the G506E mutation of CLCN5 (PMID:18322545)
• Frameshift mutation in CLCN5 protein is associated with Dent disease. (PMID:18540256)
• three classes of Dent’s disease-causing CLC-5 mutations: class 1 leads to endoplasmic reticulum retention and degradation of CLC-5; class 2 causes defects in endosomal acidification; class 3 alters endosomal distribution of CLC-5 (PMID:19019917)
• Nitrate uncoupled proton transport but mutating the highly conserved serine 168 to proline in ClC-5, led to coupled NO3(-)/H+ exchange. (PMID:19131966)
• six different truncating mutations cause premature termination of protein translation and result in a non-functional truncated protein (PMID:19546586)
• Studies showed that three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease. (PMID:19546591)
• Report novel CLCN5 mutations in patients with Dent’s disease result in altered ion currents or impaired exchanger processing. (PMID:19657328)
• Novel mutations of the CLCN5 gene including a complex allele and A 5’ UTR mutation in Dent disease 1. (PMID:19673950)
• show that the direct application of ATP, ADP and AMP in inside-out patch experiments potentiates the current mediated by ClC-5 with similar affinities. The nucleotides increase the probability of ClC-5 to be in an active, transporting state. (PMID:19713962)
• A nonsense codon of CLCN5 was found in four unrelated young males with Dent’s disease. Focal glomerusclerosis was also confirmed after kidney biopsy. (PMID:19806368)
• Interaction with KIF3B alters CLC-5 cell surface expression, chloride current, and alters albumin endocytosis. Interaction with KIF3B facilitates microtubular transport and endocytosis of CLC-5-containing vesicles away from cell surface. (PMID:19940036)
• We discuss the putative role of ClC-5 in receptor-mediated endocytosis and protein uptake by the proximal renal tubule and the possible molecular and cellular consequences of disease-causing mutations[review] (PMID:20049483)
• Suggest that CLC-5 is directly involved in endosomal acidification by exchanging endosomal Cl(-) for H(+). (PMID:20421284)
• data suggest that voltage sensing is an intrinsic property of the CLC-5 protein and that permeant anions, particularly Cl(-), modulate a voltage-dependent transition to an activated state from which Cl(-)/H(+) exchange can occur (PMID:20501796)
• Propose that protons bind to the extracellular gating glutamate E211 in CLC-5 to block transport. (PMID:20513761)
• A novel CLCN5 mutation is reported in a boy with Bartter-like syndrome and partial growth hormone deficiency. (PMID:20680351)
• ATP induces conformational changes in the carboxyl-terminal region of ClC-5. (PMID:21173145)
• Heterogeneity in the processing of CLCN5 mutants related to Dent disease. (PMID:21305656)
• protonation of the gating glutamate 211 at the central anion-binding site of ClC-5 is mediated by the proton glutamate 268. (PMID:22267722)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	clcn5a	ENSDARG00000019693
danio_rerio	clcn5b	ENSDARG00000022466
mus_musculus	Clcn5	ENSMUSG00000004317
rattus_norvegicus	Clcn5	ENSRNOG00000002862
drosophila_melanogaster	ClC-c	FBGN0036566
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN6 (ENSG00000011021), CLCN4 (ENSG00000073464), CLCN7 (ENSG00000103249), CLCN3 (ENSG00000109572), CLCN2 (ENSG00000114859), CLCNKB (ENSG00000184908), CLCNKA (ENSG00000186510), CLCN1 (ENSG00000188037)

Protein

Protein identifiers

H(+)/Cl(-) exchange transporter 5 — P51795 (reviewed: P51795)

Alternative names: Chloride channel protein 5, Chloride transporter ClC-5

All UniProt accessions (5): A0A2R8Y6C4, A0A2R8YF14, A0A2R8YGW0, P51795, V9GYG7

UniProt curated annotations — full annotation on UniProt →

Function. Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons. Important for normal acidification of the endosome lumen. May play an important role in renal tubular function. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels.

Subunit / interactions. Interacts with NEDD4 and NEDD4L.

Subcellular location. Golgi apparatus membrane. Endosome membrane. Cell membrane.

Tissue specificity. Kidney. Moderately expressed in aortic vascular smooth muscle and endothelial cells, and at a slightly higher level in the coronary vascular smooth muscle.

Post-translational modifications. Ubiquitinated by NEDD4L in the presence of albumin; which promotes endocytosis and proteasomal degradation.

Disease relevance. Hypophosphatemic rickets, X-linked recessive (XLHRR) [MIM:300554] A renal disease belonging to the ‘Dent disease complex’, a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. XLHRR patients present with rickets or osteomalacia, hypophosphatemia due to decreased renal tubular phosphate reabsorption, hypercalciuria, and low molecular weight proteinuria. Patients develop nephrocalcinosis with progressive renal failure in adulthood. Female carriers may have asymptomatic hypercalciuria or hypophosphatemia only. The disease is caused by variants affecting the gene represented in this entry. Dent disease 1 (DENT1) [MIM:300009] An X-linked recessive renal disease belonging to the ‘Dent disease complex’, a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. DENT1 patients manifest hypercalciuria, hypophosphatemia, aminoaciduria, nephrocalcinosis and nephrolithiasis, renal insufficiency leading to renal failure in adulthood, rickets (33% of patients) and osteomalacia. The disease is caused by variants affecting the gene represented in this entry. Nephrolithiasis, X-linked recessive, with renal failure (XRN) [MIM:310468] An X-linked recessive renal disease belonging to the ‘Dent disease complex’, a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. XRN patients present with hypercalciuria, nephrocalcinosis, renal stones and renal insufficiency. Patients lack urinary acidification defects, rickets, and osteomalacia. The disease is caused by variants affecting the gene represented in this entry. Low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (LMWPHN) [MIM:308990] An X-linked renal disease belonging to the ‘Dent disease complex’, a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. LMWPHN is a slowly progressive disorder. Patients tend to have hypercalciuric nephrocalcinosis without rickets or renal failure. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the chloride channel (TC 2.A.49) family. ClC-5/CLCN5 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P51795-2	1	yes
P51795-1	2

RefSeq proteins (5): NP_000075, NP_001121370, NP_001121371, NP_001259031, NP_001269092 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR001807	ClC	Family
IPR002247	Cl_channel-5	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily

Pfam: PF00571, PF00654

Catalyzed reactions (Rhea), 1 shown:

• 2 chloride(in) + H(+)(out) = 2 chloride(out) + H(+)(in) (RHEA:29567)

UniProt features (95 total): sequence variant 36, transmembrane region 10, strand 10, intramembrane region 7, binding site 6, helix 6, mutagenesis site 5, short sequence motif 3, topological domain 2, domain 2, site 2, chain 1, region of interest 1, compositionally biased region 1, splice variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2J9L	X-RAY DIFFRACTION	2.3
2JA3	X-RAY DIFFRACTION	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51795-F1	80.48	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 281 (mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking h(+) and cl(-) transport); 338 (mediates proton transfer from the protein to the inner aqueous phase)

Ligand- & substrate-binding residues (6): 238; 525; 628; 666; 687–689; 794–797

Mutagenesis-validated functional residues (5):

Position	Phenotype
281	abolishes proton transport, but not chloride transport.
687	strongly decreased affinity for atp, but no effect on chloride transport.
688	no effect atp binding or chloride transport.
742	abolishes interaction with nedd4 and nedd4l.
797	strongly decreased affinity for atp, but no effect on chloride transport.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 361 (showing top): BENPORATH_ES_WITH_H3K27ME3, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOCC_VACUOLAR_MEMBRANE, GOBP_INORGANIC_ANION_TRANSPORT, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, CTATGCA_MIR153, GOBP_CHLORIDE_TRANSPORT, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP, TGANTCA_AP1_C, TGACATY_UNKNOWN, PPAR_DR1_Q2, ATF3_Q6, GATA1_04, USF_02

GO Biological Process (7): renal system process (GO:0003014), chloride transport (GO:0006821), endocytosis (GO:0006897), monoatomic ion transmembrane transport (GO:0034220), monoatomic ion transport (GO:0006811), transmembrane transport (GO:0055085), chloride transmembrane transport (GO:1902476)

GO Molecular Function (8): voltage-gated chloride channel activity (GO:0005247), ATP binding (GO:0005524), antiporter activity (GO:0015297), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), chloride channel activity (GO:0005254), protein binding (GO:0005515), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (11): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), early endosome (GO:0005769), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), endosome membrane (GO:0010008), membrane (GO:0016020), apical part of cell (GO:0045177), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
transport	2
bounding membrane of organelle	2
endosome	2
cytoplasm	2
endomembrane system	2
system process	1
monoatomic anion transport	1
inorganic anion transport	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
chloride transport	1
monoatomic anion transmembrane transport	1
chloride channel activity	1
voltage-gated monoatomic anion channel activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
secondary active transmembrane transporter activity	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
binding	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1
Golgi apparatus	1
lysosome	1
lytic vacuole membrane	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
exocytic vesicle	1
presynapse	1
cytoplasmic vesicle membrane	1

Protein interactions and networks

STRING

1255 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCN5	OCRL	Q01968	937
CLCN5	LRP2	P98164	933
CLCN5	CUBN	O60494	868
CLCN5	SLC34A3	Q8N130	835
CLCN5	SLC9A3	P48764	814
CLCN5	CFL2	Q9Y281	809
CLCN5	CFL1	P23528	808
CLCN5	BSND	Q8WZ55	804
CLCN5	KCNJ1	P48048	716
CLCN5	SLC12A1	Q13621	697
CLCN5	PHEX	P78562	693
CLCN5	B2M	P01884	640
CLCN5	ENPP1	P22413	640
CLCN5	SLC12A3	P55017	637
CLCN5	CASR	P41180	632

IntAct

39 interactions, top by confidence:

A	B	Type	Score
TMEM9B	DNAJC13	psi-mi:“MI:0914”(association)	0.640
CLCN5	KIF3B	psi-mi:“MI:0915”(physical association)	0.600
KIF3B	CLCN5	psi-mi:“MI:0403”(colocalization)	0.600
CLCN5	CLCN5	psi-mi:“MI:0407”(direct interaction)	0.560
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
CLCN5	CREB3	psi-mi:“MI:0915”(physical association)	0.490
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
RAB7A	SCAMP3	psi-mi:“MI:0914”(association)	0.350
VTI1A	STX16	psi-mi:“MI:0914”(association)	0.350
LGALS9B	ABCC4	psi-mi:“MI:0914”(association)	0.350
FEM1A	RNF113A	psi-mi:“MI:0914”(association)	0.350
TMEM9B	STX10	psi-mi:“MI:0914”(association)	0.350
CLCN5	LGALS3	psi-mi:“MI:0914”(association)	0.350
TMEM9B	NBAS	psi-mi:“MI:0914”(association)	0.350
FEM1A	LAD1	psi-mi:“MI:0914”(association)	0.350
FEM1A	DHRS3	psi-mi:“MI:0914”(association)	0.350
LETMD1	GOSR2	psi-mi:“MI:0914”(association)	0.350
ACVR1	NBAS	psi-mi:“MI:0914”(association)	0.350
TMEM9B	FANCG	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
NIPAL3	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (51): CLCN5 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), CLCN5 (Affinity Capture-RNA), APPL2 (Affinity Capture-MS), LGALS3 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), TMEM9 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS), CLCN5 (Affinity Capture-MS)

ESM2 similar proteins: A1A5G6, A3RL54, B8K1V7, O16452, O18894, P07038, P25286, P51790, P51791, P51792, P51795, P51796, Q07421, Q09573, Q28677, Q29466, Q2QY12, Q2R041, Q2RAS0, Q2UVJ5, Q3YL57, Q56XP4, Q5R422, Q5RBK4, Q5RDJ7, Q5RK27, Q63632, Q657W3, Q68KI4, Q6H641, Q6Z0E2, Q84WG1, Q8AVM5, Q8S397, Q920R6, Q924N4, Q93050, Q9GKE7, Q9I8D0, Q9JIS8

Diamond homologs: O18894, O60159, P0C197, P35525, P37020, P51788, P51789, P51790, P51791, P51792, P51793, P51794, P51795, P51796, P92943, Q4PKH3, Q54AX6, Q54C67, Q5RBK4, Q5RDJ7, Q61418, Q75JF3, Q99P66, Q9BMK9, Q9GKE7, Q9MZT1, Q9R0A1, Q9R279, Q9TTU3, Q9VGH7, Q9WU45, Q9WVD4, O35454, O70496, P51797, P51798, P51799, P92942, Q1ZXJ0, Q86AZ6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NEDD4L	“down-regulates quantity by destabilization”	CLCN5	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein transport	8	9.2×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

653 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	81
Likely pathogenic	60
Uncertain significance	254
Likely benign	87
Benign	35

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072816	NC_000023.10:g.(?49845231)(49851547_?)del	Pathogenic
1074397	NM_001127898.4(CLCN5):c.1092dup (p.Ile365fs)	Pathogenic
11796	NM_001127898.4(CLCN5):c.1047G>A (p.Trp349Ter)	Pathogenic
11797	NM_001127898.4(CLCN5):c.2152C>T (p.Arg718Ter)	Pathogenic
11798	NM_001127898.4(CLCN5):c.809T>G (p.Leu270Arg)	Pathogenic
11799	NM_001127898.4(CLCN5):c.1768T>C (p.Ser590Pro)	Pathogenic
11801	NM_001127898.4(CLCN5):c.1727G>A (p.Gly576Glu)	Pathogenic
11802	NM_001127898.4(CLCN5):c.941C>T (p.Ser314Leu)	Pathogenic
11803	NM_001127898.4(CLCN5):c.1238G>A (p.Trp413Ter)	Pathogenic
11804	NM_001127898.4(CLCN5):c.2295del (p.Met766fs)	Pathogenic
11805	NM_001127898.4(CLCN5):c.1049G>C (p.Arg350Pro)	Pathogenic
11806	NM_001127898.4(CLCN5):c.380G>T (p.Gly127Val)	Pathogenic
11807	NG_007159.3:g.173054_173069dupinsAluYa5	Pathogenic
11808	NM_001127898.4(CLCN5):c.989G>T (p.Gly330Val)	Pathogenic
1210259	NM_001127898.4(CLCN5):c.976G>C (p.Gly326Arg)	Pathogenic
1210260	NM_001127898.4(CLCN5):c.933+2T>C	Pathogenic
1419029	NM_001127898.4(CLCN5):c.2297del (p.Met766fs)	Pathogenic
1451923	NC_000023.10:g.(?49834581)(49840657_?)del	Pathogenic
1505876	NM_001127898.4(CLCN5):c.1009G>A (p.Glu337Lys)	Pathogenic
1685636	NM_001127898.4(CLCN5):c.1386_1387del (p.Cys462fs)	Pathogenic
1804929	NM_001127898.4(CLCN5):c.1452del (p.Glu484fs)	Pathogenic
18451	NM_001127898.4(CLCN5):c.1557+1G>T	Pathogenic
2000809	NM_001127898.4(CLCN5):c.467_471del (p.Lys156fs)	Pathogenic
2032286	NM_001127898.4(CLCN5):c.1001dup (p.Ser335fs)	Pathogenic
2040636	NM_001127898.4(CLCN5):c.1478dup (p.Val494fs)	Pathogenic
207996	NM_001127898.4(CLCN5):c.1249C>T (p.Arg417Ter)	Pathogenic
207997	NM_001127898.4(CLCN5):c.1609C>T (p.Arg537Ter)	Pathogenic
207999	NM_001127898.4(CLCN5):c.2119C>T (p.Arg707Ter)	Pathogenic
208000	NM_001127898.4(CLCN5):c.2362C>T (p.Arg788Ter)	Pathogenic
208001	NG_007159.3:g.(?162979)(164232_?)del	Pathogenic

SpliceAI

2292 predictions. Top by Δscore:

Variant	Effect	Δscore
X:50069872:A:AG	acceptor_gain	1.0000
X:50069873:A:G	acceptor_gain	1.0000
X:50069874:TACA:T	acceptor_loss	1.0000
X:50069875:A:AG	acceptor_gain	1.0000
X:50069876:C:G	acceptor_gain	1.0000
X:50069877:A:AG	acceptor_gain	1.0000
X:50069877:AGAG:A	acceptor_gain	1.0000
X:50069878:G:GT	acceptor_gain	1.0000
X:50069878:GA:G	acceptor_gain	1.0000
X:50069878:GAGG:G	acceptor_gain	1.0000
X:50069878:GAGGA:G	acceptor_gain	1.0000
X:50070028:GAG:G	donor_gain	1.0000
X:50070032:T:TC	donor_loss	1.0000
X:50085974:TTTTA:T	acceptor_loss	1.0000
X:50085976:TTA:T	acceptor_loss	1.0000
X:50085977:TA:T	acceptor_loss	1.0000
X:50085978:AGGT:A	acceptor_loss	1.0000
X:50088694:GCA:G	acceptor_loss	1.0000
X:50088695:CAG:C	acceptor_loss	1.0000
X:50088696:A:AC	acceptor_loss	1.0000
X:50088696:A:AG	acceptor_gain	1.0000
X:50088697:G:GG	acceptor_gain	1.0000
X:50088697:GATC:G	acceptor_gain	1.0000
X:50088697:GATCC:G	acceptor_gain	1.0000
X:50088827:G:GT	donor_gain	1.0000
X:50090110:TTGCA:T	acceptor_loss	1.0000
X:50090111:TGCA:T	acceptor_loss	1.0000
X:50090112:GCA:G	acceptor_loss	1.0000
X:50090113:CA:C	acceptor_loss	1.0000
X:50090114:AGG:A	acceptor_loss	1.0000

AlphaMissense

5370 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:50069987:A:T	D91V	1.000
X:50069989:T:A	W92R	1.000
X:50069989:T:C	W92R	1.000
X:50069991:G:C	W92C	1.000
X:50069991:G:T	W92C	1.000
X:50072555:T:A	W128R	1.000
X:50072555:T:C	W128R	1.000
X:50072576:G:A	G135R	1.000
X:50072576:G:C	G135R	1.000
X:50072576:G:T	G135W	1.000
X:50072577:G:A	G135E	1.000
X:50075795:G:A	G139D	1.000
X:50075946:G:C	W189C	1.000
X:50075946:G:T	W189C	1.000
X:50080694:C:A	A235D	1.000
X:50080705:G:A	G239R	1.000
X:50080705:G:C	G239R	1.000
X:50080706:G:A	G239E	1.000
X:50081646:A:C	K244N	1.000
X:50081646:A:T	K244N	1.000
X:50081654:T:G	L247W	1.000
X:50081659:G:C	G249R	1.000
X:50081659:G:T	G249C	1.000
X:50081660:G:A	G249D	1.000
X:50081660:G:T	G249V	1.000
X:50081662:T:C	F250L	1.000
X:50081663:T:C	F250S	1.000
X:50081664:C:A	F250L	1.000
X:50081664:C:G	F250L	1.000
X:50081749:G:C	G279R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002582 (X:50084104 T>G), RS1000029033 (X:50074248 T>G), RS1000032288 (X:49927928 C>T), RS1000058925 (X:50095969 C>A), RS1000077406 (X:49938242 C>A), RS1000127308 (X:50093815 C>G,T), RS1000250181 (X:50075886 A>G), RS1000285759 (X:50051872 G>A), RS1000308738 (X:49990581 G>A), RS1000309775 (X:50060284 A>G), RS1000345200 (X:49979525 T>G), RS1000455864 (X:49991012 T>C), RS1000464656 (X:49929389 G>A,T), RS1000551115 (X:50009618 T>C), RS1000558556 (X:50043573 T>C)

Disease associations

OMIM: gene MIM:300008 | disease phenotypes: MIM:300009, MIM:300554, MIM:308990, MIM:310468, MIM:307800, MIM:158810

GenCC curated gene-disease

Disease	Classification	Inheritance
Dent disease type 1	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Dent disease type 1	Definitive	XL

Mondo (8): Dent disease type 1 (MONDO:0010225), hypophosphatemic rickets, X-linked recessive (MONDO:0010358), proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis (MONDO:0010644), nephrolithiasis, X-linked recessive, with renal failure (MONDO:0010687), X-linked dominant hypophosphatemic rickets (MONDO:0010619), Dent disease (MONDO:0015612), Bethlem myopathy 1A (MONDO:0024530), nephrotic syndrome (MONDO:0005377)

Orphanet (4): Dent disease (Orphanet:1652), Dent disease type 1 (Orphanet:93622), X-linked hypophosphatemia (Orphanet:89936), Bethlem muscular dystrophy (Orphanet:610)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000083	Renal insufficiency
HP:0000092	Renal tubular atrophy
HP:0000096	Glomerular sclerosis
HP:0000097	Focal segmental glomerulosclerosis
HP:0000114	Proximal tubulopathy
HP:0000117	Renal phosphate wasting
HP:0000121	Nephrocalcinosis
HP:0000787	Nephrolithiasis
HP:0001419	X-linked recessive inheritance
HP:0002148	Hypophosphatemia
HP:0002150	Hypercalciuria
HP:0002653	Bone pain
HP:0002663	Delayed epiphyseal ossification
HP:0002748	Rickets
HP:0002749	Osteomalacia
HP:0002752	Sparse bone trabeculae
HP:0002753	Thin bony cortex
HP:0002757	Recurrent fractures
HP:0002907	Microscopic hematuria
HP:0002979	Bowing of the legs
HP:0002980	Femoral bowing
HP:0002982	Tibial bowing
HP:0003013	Bulging epiphyses
HP:0003020	Enlargement of the wrists
HP:0003025	Metaphyseal irregularity
HP:0003029	Enlargement of the ankles
HP:0003076	Glycosuria
HP:0003109	Hyperphosphaturia
HP:0003126	Low-molecular-weight proteinuria
HP:0003158	Hyposthenuria

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST008156_16	Hip circumference adjusted for BMI	3.000000e-07
GCST008163_137	Height	8.000000e-06
GCST90002403_715	Red blood cell count	1.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0004305	erythrocyte count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D057973	Dent Disease	C12.050.351.968.419.815.364; C12.200.777.419.815.364; C12.950.419.815.364; C16.320.322.100; C16.320.831.271
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
C545036	Low Molecular Weight Proteinuria with Hypercalciuria and Nephrocalcinosis (supp.)
C562901	Nephrolithiasis, X-Linked Recessive, with Renal Failure (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — ClC family

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
bisphenol A	affects methylation, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Doxorubicin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	decreases expression	1
Vorinostat	affects cotreatment, increases expression	1
Amiodarone	increases expression	1
Folic Acid	decreases expression	1
Formaldehyde	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Testosterone	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1

Cellosaurus cell lines

6 cell lines: 3 induced pluripotent stem cell, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4YB	WMUi016-A	Induced pluripotent stem cell	Male
CVCL_B3MT	NCKDi003-A	Induced pluripotent stem cell	Female
CVCL_D0D4	CMCi011-A	Induced pluripotent stem cell	Male
CVCL_E0A9	Ubigene HeLa CLCN5 KO	Cancer cell line	Female
CVCL_E1TS	HAP1 CLCN5 (-) 2	Cancer cell line	Male
CVCL_XM82	HAP1 CLCN5 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

160 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03820518	PHASE4	UNKNOWN	Using Different Doses of Active Vitamin D Combined With Neutral Phosphate in Children With X-linked Hypophosphatemia
NCT04146935	PHASE4	COMPLETED	Examining the Effect of Burosumab on Muscle Function
NCT04419363	PHASE4	UNKNOWN	Burosumab in Children and Adolescents With X-linked Hypophosphatemia
NCT04842019	PHASE4	COMPLETED	Study to Assess the Safety, Pharmacokinetics and Efficacy of KRN23 in Adult Chinese Patients With XLH
NCT04842032	PHASE4	COMPLETED	Study to Assess the Safety, Pharmacokinetics and Efficacy of KRN23 in Pediatric Chinese Patients With XLH
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT02526160	PHASE3	COMPLETED	Study of KRN23 in Adults With X-linked Hypophosphatemia (XLH)
NCT02537431	PHASE3	COMPLETED	Open Label Study of KRN23 on Osteomalacia in Adults With X-linked Hypophosphatemia (XLH)
NCT02915705	PHASE3	COMPLETED	Efficacy and Safety of Burosumab Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With XLH
NCT03233126	PHASE3	COMPLETED	A Study of KRN23 in Pediatric Patients With X-linked Hypophosphatemic Rickets/Osteomalacia
NCT03920072	PHASE3	COMPLETED	Study of the Anti-FGF23 Antibody, Burosumab, in Adults With XLH
NCT04308096	PHASE3	COMPLETED	A Study of KRN23 in Adult and Pediatric Patients With X-linked Hypophosphatemic Rickets/Osteomalacia
NCT04695860	PHASE3	COMPLETED	Anti-FGF23 (Burosumab) in Adult Patients With XLH
NCT04872907	PHASE3	UNKNOWN	Prevention of Spontaneous Dental Abscesses in Children With X-linked Hypophosphatemia : a RCT
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT02163577	PHASE2	COMPLETED	Study of KRN23 (Burosumab), a Recombinant Fully Human Monoclonal Antibody Against Fibroblast Growth Factor 23 (FGF23), in Pediatric Subjects With X-linked Hypophosphatemia (XLH)