CLCNKB

Summary

CLCNKB (chloride voltage-gated channel Kb, HGNC:2027) is a protein-coding gene on chromosome 1p36.13, encoding Chloride channel protein ClC-Kb (P51801). Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.

The protein encoded by this gene is a member of the family of voltage-gated chloride channels. Chloride channels have several functions, including the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. This gene is expressed predominantly in the kidney and may be important for renal salt reabsorption. Mutations in this gene are associated with autosomal recessive Bartter syndrome type 3 (BS3). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1188 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bartter disease type 3 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 593 total — 32 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 125
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000085

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2027
Approved symbol	CLCNKB
Name	chloride voltage-gated channel Kb
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	hClC-Kb, CLCKB, ClC-K2, ClC-Kb
Ensembl gene	ENSG00000184908
Ensembl biotype	protein_coding
OMIM	602023
Entrez	1188

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 26 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000375667, ENST00000375679, ENST00000431772, ENST00000682338, ENST00000682793, ENST00000682838, ENST00000683578, ENST00000683606, ENST00000683661, ENST00000684324, ENST00000684545, ENST00000684624, ENST00000684650, ENST00000684714, ENST00000684731, ENST00000906258, ENST00000906259, ENST00000906260, ENST00000906261, ENST00000906262, ENST00000906263, ENST00000906264, ENST00000906265, ENST00000906266, ENST00000906267, ENST00000906268, ENST00000906269, ENST00000906270, ENST00000906271, ENST00000906272, ENST00000906273, ENST00000906274, ENST00000906275

RefSeq mRNA: 2 — MANE Select: NM_000085 NM_000085, NM_001165945

CCDS: CCDS168, CCDS57974

Canonical transcript exons

ENST00000375679 — 20 exons

Exon	Start	End
ENSE00001295583	16053639	16053772
ENSE00001623837	16049618	16049702
ENSE00001629577	16050875	16051048
ENSE00001629974	16056422	16056508
ENSE00001638743	16046535	16046663
ENSE00001638879	16052198	16052411
ENSE00001644923	16055435	16055523
ENSE00001681519	16047905	16048044
ENSE00001682331	16055675	16055758
ENSE00001682955	16051710	16051820
ENSE00001688733	16048504	16048582
ENSE00001691281	16050516	16050600
ENSE00001705434	16048343	16048420
ENSE00001713263	16049120	16049245
ENSE00001734426	16049815	16049916
ENSE00001788569	16051478	16051547
ENSE00001789972	16045558	16045686
ENSE00001877330	16043782	16043880
ENSE00002725418	16044486	16044592
ENSE00003900225	16056869	16057308

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 98.96.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5702 / max 100.7985, expressed in 221 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
960	0.2523	161
956	0.1196	14
959	0.0636	28
201375	0.0555	23
958	0.0410	10
957	0.0324	8
955	0.0060	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	98.96	gold quality
adult mammalian kidney	UBERON:0000082	97.10	gold quality
metanephros cortex	UBERON:0010533	95.22	gold quality
kidney	UBERON:0002113	90.11	gold quality
adult organism	UBERON:0007023	89.57	gold quality
parotid gland	UBERON:0001831	88.19	gold quality
sperm	CL:0000019	86.52	gold quality
male germ cell	CL:0000015	83.42	gold quality
right lobe of thyroid gland	UBERON:0001119	83.14	gold quality
left lobe of thyroid gland	UBERON:0001120	82.98	gold quality
thyroid gland	UBERON:0002046	82.75	gold quality
cortex of kidney	UBERON:0001225	80.51	gold quality
apex of heart	UBERON:0002098	79.57	gold quality
metanephros	UBERON:0000081	78.70	gold quality
saliva-secreting gland	UBERON:0001044	77.67	gold quality
oocyte	CL:0000023	76.48	silver quality
cerebellar hemisphere	UBERON:0002245	76.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.40	gold quality
cerebellar cortex	UBERON:0002129	76.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.81	gold quality
cerebellum	UBERON:0002037	75.48	gold quality
nephron tubule	UBERON:0001231	75.18	silver quality
minor salivary gland	UBERON:0001830	74.32	gold quality
kidney epithelium	UBERON:0004819	74.25	silver quality
triceps brachii	UBERON:0001509	73.89	gold quality
mouth mucosa	UBERON:0003729	73.34	gold quality
gluteal muscle	UBERON:0002000	71.49	gold quality
right atrium auricular region	UBERON:0006631	71.48	gold quality
gingival epithelium	UBERON:0001949	71.26	gold quality
cerebellar vermis	UBERON:0004720	70.84	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1075.15
E-CURD-119	yes	43.36
E-HCAD-10	yes	14.81
E-CURD-114	yes	11.40
E-ANND-3	no	2.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting CLCNKB, 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-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-4741	97.69	64.14	883
HSA-MIR-6514-3P	97.52	66.50	808
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-1292-5P	96.74	62.14	238
HSA-MIR-6894-3P	96.73	65.64	798

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• DNA mutational analysis of CLCNKB in Bartter syndrome type 3. (PMID:11865110)
• presence of Gitelman and Bartter syndrome and CBS phenotypes, in a kindred with the CLCNKB R438H mutation. (PMID:12472765)
• CLCKB expression is demonstrated in stria vascularis, spiral ligament and limbal fibrocytes, interdental cells and satellite cells of spiral ganglion neurons of mice harboring enhanced green fluorescence protein gene driven by the human CLCKB promoter. (PMID:14502078)
• Genetic heterogeneity of ClC-Kb chloride channels correlates with functional heterogeneity, which assigns ClC-Kb to a set of genes potentially relevant for polygenic salt-sensitivity of blood pressure regulation. (PMID:14675050)
• Combined impairment of ClC-Ka and ClC-Kb results in phenotype that mimics neonatal Barrter’s syndrome with deafness (PMID:15044642)
• The mutation ClC-Kb(T481S) of the renal epithelial Cl- channel ClC-Kb strongly activates ClC-Kb chloride channel function in vitro and may predispose to the development of essential hypertension in vivo. (PMID:15148291)
• There is no association with hypertension of CLCNKB polymorphism at a hypertension locus on chromosome 1p36. (PMID:16003175)
• confirms a weak genotype-phenotype correlation in patients with CLCNKB mutations and supports the founder effect of the A204T mutation in Spain (PMID:16391491)
• Barttin modulates trafficking and function of ClC-K1 and ClC-Kb channels (PMID:16849430)
• Identification of a novel mutation of the CLCNKB gene, DeltaL130 associated with Bartter syndrome. (PMID:16902263)
• Results identify large heterozygous deletion mutations in the CLCNKB gene in patients with type III Bartter syndrome. (PMID:17622951)
• roles of Thr418Ser polymorphism of the CLCNKB gene and Arg904Gln polymorphism in the TSC gene on essential hypertension need to be explored in other ethnic groups (PMID:17997379)
• Disruption of the gene encoding Barttin, BSND, results in a ‘double knockout’ of the functions of both ClCKA and ClCKB, manifesting as Bartter syndrome type IV with sensorineural deafness and an especially severe salt-losing phenotype. (PMID:18094726)
• ClC-Ka and ClC-Kb differ in how conformational changes are translated to the extracellular domain, despite the fact that the cytoplasmic domains share the same quaternary structure (PMID:18648499)
• In a large cohort of ante/neonatal Bartter syndrome, deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. (PMID:19096086)
• Threonine change to serine at position 481 in CLCNKB is associated with essential hypertension in males within the Ghanaian population. (PMID:19226700)
• Three novel CLCNKB mutations are identified associated with classic Bartter syndrome with a role in altering the functional properties of ClC-Kb channels. (PMID:19807735)
• Identify a protein region that is involved in calcium binding and that is likely undergoing conformational changes underlying the complex gating of CLC-K channels. (PMID:20805576)
• novel missense variant of the CLCNKB gene in two patients with type III Bartter syndrome (PMID:21479528)
• four mutations in the CLCNKB gene, among patients suffering from bartter and Gitelman syndromes (PMID:21631963)
• there was no significant association between the SLC12A3 R904Q variant and the ClC-Kb-T481S variant and essential hypertension in Mongolian and Han populations in Inner Mongolia (PMID:21644212)
• CLCNKB mutations are associated with Bartter syndrome. (PMID:21865213)
• expands the association between CLCNKB and essential hypertension to a non-European ancestry population (PMID:22578033)
• This article presents the case of a patient with hypokalaemia caused by CLCNKB gene mutation hard to categorise as GS or BS type 3. (PMID:23345488)
• study investigated the functional consequences of seven mutations; four mutants carried no current whereas others displayed a 30-60 percent reduction in conductance as compared with wild-type ClC-Kb (PMID:23703872)
• we report here for the first time that ClC-Kb disease-causing mutations located around the selectivity filter can result in both reduced surface expression and hyperactivity in heterologous expression systems (PMID:24271511)
• HEK293 cells the potentiating effect of niflumic acid (NFA) on CLC-Ka/barttin and CLC-Kb/barttin channels seems to be absent while the blocking efficacy of niflumic acid and benzofuran derivatives observed in oocytes is preserved (PMID:24863058)
• Single loci of tag Single Nucleotide Polymorphisms of CLCNKA_B are not enough to increase the Essential Hypertension susceptibility, the combination of CLCNKA SNP, salt, marine products, meat, edible oil consumption is associated with elevated risk (PMID:25919862)
• Case Report: 2 mutations in the CLCNKB gene, leading to a molecular diagnosis of Bartter syndrome type III in case of sudden infant death. (PMID:25923035)
• R8W and G47R, two naturally occurring barttin mutations identified in patients with Bartter syndrome type IV, reduce barttin palmitoylation and CLC-K/barttin channel activity. (PMID:26013830)
• These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit (PMID:26063802)
• results demonstrate that the carboxyl terminus of hClC-Kb is not part of the binding site for barttin, but functionally modifies the interplay with barttin. (PMID:26453302)
• Five patients had 1 or more mutations in CLCNKB, of whom 3 had homozygous mutations and 2 had single heterozygous mutations and only in CLCNKB had hypocalciuria. (PMID:26770037)
• Taking advantage of the largest number of functional results of CLCNKB mutations, we reveal the functionally important domains and severe mutational spots of the hClC-Kb channel and establish the genotype-phenotype association in classic Bartter’s Syndrome. (PMID:28555925)
• results suggested that the compound defective mutations of the CLCNKB gene are the molecular mechanism of the two classic Bartter syndrome siblings (PMID:29442545)
• Nine variants in the chloride voltagegated channel Kb (CLCNKB) gene were detected, including eight sequence variants and one whole CLCNKB gene deletion. One sequence variant (c.1967T>C) was novel, whereas the remaining variants (c.595G>T, c.908A>C, c.1004T>C, c.1312C>T, c.1334_1335delCT and c.1718C>A) and the whole gene deletion had been previously reported. (PMID:31115572)
• Bartter syndrome (BS) is a rare autosomal recessive disorder of salt reabsorption at the thick ascending limb of the Henle loop, characterized by hypokalemia, salt loss, metabolic alkalosis, hyperreninemic hyperaldosteronism with normal blood pressure. BS type III, often known as classic BS (CBS), is caused by loss-of-function mutations in CLCNKB (chloride voltage-gated channel Kb) encoding basolateral ClC-Kb. (PMID:31409296)
• Analysis of CLCNKB mutations at dimer-interface, calcium-binding site, and pore reveals a variety of functional alterations in ClC-Kb channel leading to Bartter syndrome. (PMID:31803959)
• Thirteen novel CLCNKB variants and genotype/phenotype association study in 42 Chinese patients with Bartter syndrome type 3. (PMID:31834604)
• Simultaneous Homozygous Mutations in SLC12A3 and CLCNKB in an Inbred Chinese Pedigree. (PMID:33807568)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Clcnkb	ENSMUSG00000006216
mus_musculus	Clcnka	ENSMUSG00000033770
rattus_norvegicus	Clcnkb	ENSRNOG00000009897
rattus_norvegicus	Clcnka	ENSRNOG00000052368
drosophila_melanogaster	ClC-c	FBGN0036566
drosophila_melanogaster	ClC-a	FBGN0051116
caenorhabditis_elegans		WBGENE00000530
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN6 (ENSG00000011021), CLCN4 (ENSG00000073464), CLCN7 (ENSG00000103249), CLCN3 (ENSG00000109572), CLCN2 (ENSG00000114859), CLCN5 (ENSG00000171365), CLCNKA (ENSG00000186510), CLCN1 (ENSG00000188037)

Protein

Protein identifiers

Chloride channel protein ClC-Kb — P51801 (reviewed: P51801)

Alternative names: ClC-K2

All UniProt accessions (5): A0A804HI21, A0A804HJB2, A0A804HJU7, P51801, Q5T5Q6

UniProt curated annotations — full annotation on UniProt →

Function. Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide. Forms a homodimeric channel where each subunit has its own ion conduction pathway. May conduct double-barreled currents controlled by two types of gates, two fast gates that control each subunit independently and a slow common gate that opens and shuts off both subunits simultaneously. Assembles with the regulatory subunit BSND/Barttin for sorting at the basolateral plasma membrane domain and functional switch to the ion conducting state. CLCNKB:BSND channels display mostly a linear current-voltage relationship controlled by common gate. Mediates chloride conductance along nephron segments, namely the thick ascending limb of Henle’s loop, convoluted tubule and the collecting duct, contributing to the maintenance of systemic acid-base and electrolyte homeostasis. Conducts chloride currents in the stria vascularis of the inner ear to establish the endocochlear potential necessary for normal hearing.

Subunit / interactions. Homodimer. Interacts with BSND.

Subcellular location. Basolateral cell membrane.

Post-translational modifications. N-glycosylated.

Disease relevance. Bartter syndrome 3 (BARTS3) [MIM:607364] A form of Bartter syndrome, an autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. The disease is caused by variants affecting the gene represented in this entry. Bartter syndrome 4B, neonatal, with sensorineural deafness (BARTS4B) [MIM:613090] A digenic form of Bartter syndrome, an autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. BARTS4B is associated with sensorineural deafness. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Loss-of-function of both CLCNKA and CLCNKB results in the disease phenotype.

Activity regulation. Activated by extracellular Ca(2+) and inhibited by extracellular acidic pH.

Miscellaneous. Compared with CLCNKA/BSND, CLCNKB/BSND is more sensitive to pH and less responsive to Ca(2+).

Similarity. Belongs to the chloride channel (TC 2.A.49) family. CLCNKB subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P51801-1	1	yes
P51801-2	2

RefSeq proteins (2): NP_000076, NP_001159417 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR001807	ClC	Family
IPR002250	Cl_channel-K	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily
IPR050970	Cl_channel_volt-gated	Family

Pfam: PF00571, PF00654

Catalyzed reactions (Rhea), 4 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• nitrate(in) = nitrate(out) (RHEA:34923)
• iodide(out) = iodide(in) (RHEA:66324)
• bromide(in) = bromide(out) (RHEA:75383)

UniProt features (58 total): sequence variant 28, transmembrane region 10, binding site 6, intramembrane region 4, splice variant 3, topological domain 2, domain 2, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51801-F1	87.16	0.60

Functional residue map

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

Ligand- & substrate-binding residues (6): 121; 259; 261; 278; 281; 426

Glycosylation sites (1): 193

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 327 (showing top): MODULE_416, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, DELYS_THYROID_CANCER_DN, GOBP_TRANSEPITHELIAL_TRANSPORT, MODULE_99, GOBP_RENAL_ABSORPTION, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, GOBP_RENAL_SYSTEM_PROCESS, GOCC_CHLORIDE_CHANNEL_COMPLEX, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (8): chloride transport (GO:0006821), transepithelial chloride transport (GO:0030321), renal absorption (GO:0070293), renal sodium ion absorption (GO:0070294), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), chloride transmembrane transport (GO:1902476)

GO Molecular Function (5): voltage-gated chloride channel activity (GO:0005247), chloride channel activity (GO:0005254), metal ion binding (GO:0046872), protein binding (GO:0005515), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (4): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), chloride channel complex (GO:0034707), membrane (GO:0016020)

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
chloride transport	2
transport	2
monoatomic anion transport	1
inorganic anion transport	1
transepithelial transport	1
renal system process	1
renal sodium ion transport	1
renal absorption	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
monoatomic anion transmembrane transport	1
chloride channel activity	1
voltage-gated monoatomic anion channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
cation binding	1
binding	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
monoatomic ion channel complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

763 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCNKB	BSND	Q8WZ55	997
CLCNKB	SLC12A3	P55017	958
CLCNKB	SLC12A1	Q13621	946
CLCNKB	KCNJ1	P48048	933
CLCNKB	KLF15	Q9UIH9	762
CLCNKB	CASR	P41180	663
CLCNKB	REN	P00797	650
CLCNKB	CLDN16	Q9Y5I7	629
CLCNKB	TRPM6	Q9BX84	621
CLCNKB	SLC9A1	P19634	599
CLCNKB	KCNJ10	P78508	595
CLCNKB	MAZ	P56270	594
CLCNKB	WNK4	Q96J92	588
CLCNKB	CLDN19	Q8N6F1	580
CLCNKB	MAGED2	Q9UNF1	570

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CLCNKB	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
CLCNKB	CFTR	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (1): CLCNKB (PCA)

ESM2 similar proteins: A2BFP5, D3ZJ25, F1NXU8, G3V8V5, O35454, O88454, O97704, P35525, P51788, P51789, P51797, P51800, P51801, P51802, P51803, P51804, P51912, Q06393, Q06495, Q06496, Q1HAQ0, Q28620, Q3SWT5, Q3TD49, Q3TFD2, Q49SH1, Q5PQL3, Q60825, Q62052, Q6AXS0, Q6J4K2, Q71RS6, Q7TN37, Q80SU6, Q8C261, Q8K4R8, Q8N130, Q8NF37, Q8R1P5, Q921R8

Diamond homologs: A1A7K1, A4TPW7, A5F0D5, A6T4V9, A7FM08, A7MGR4, A7N6K9, A7ZHP7, A7ZM51, A7ZWA3, A8ALD3, A9MPK6, A9N0Q1, A9R1E4, B1IQI5, B1IQZ8, B1JK21, B1LEU5, B1LGV8, B1XD25, B1XF57, B2K549, B2U1Q2, B2U300, B4SUY5, B4TK31, B4TXQ7, B5BL83, B5F8R6, B5FHR3, B5FJ02, B5R3G7, B5RHE1, B5Y1L4, B5Z0D5, B5Z428, B6HZD1, B7L5E4, B7LGL7, B7LWB6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	21
Uncertain significance	186
Likely benign	173
Benign	135

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1179108	GRCh37/hg19 1p36.13(chr1:16370960-16383841)	Pathogenic
1805279	NM_000085.5(CLCNKB):c.619del (p.Val207fs)	Pathogenic
1917648	NM_000085.5(CLCNKB):c.1183_1184dup (p.Phe396fs)	Pathogenic
1934472	NM_000085.5(CLCNKB):c.1438del (p.His480fs)	Pathogenic
2055600	NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His)	Pathogenic
2081409	NM_000085.5(CLCNKB):c.498+2T>G	Pathogenic
2151863	NM_000085.5(CLCNKB):c.498+1G>C	Pathogenic
2202706	NM_000085.5(CLCNKB):c.1172G>A (p.Trp391Ter)	Pathogenic
2733831	NM_000085.5(CLCNKB):c.685dup (p.Ser229fs)	Pathogenic
2881305	NM_000085.5(CLCNKB):c.632_633del (p.Thr211fs)	Pathogenic
2965395	NM_000085.5(CLCNKB):c.843del (p.Ile282fs)	Pathogenic
2990998	NM_000085.5(CLCNKB):c.547_563del (p.Val183fs)	Pathogenic
3336458	NC_000001.10:g.(?16370276)(16377096_16377369)del	Pathogenic
3366530	NC_000001.10:g.(?16370276)(16372182_16373029)del	Pathogenic
3374899	NC_000001.10:g.(?16370276)(16383804_?)del	Pathogenic
3714992	NM_000085.5(CLCNKB):c.735C>A (p.Cys245Ter)	Pathogenic
4078108	NM_000085.5(CLCNKB):c.867-2del	Pathogenic
447098	NM_000085.5(CLCNKB):c.1783C>T (p.Arg595Ter)	Pathogenic
447106	NM_000085.5(CLCNKB):c.73del (p.Cys25fs)	Pathogenic
4540802	NM_000085.5(CLCNKB):c.1935_1936del (p.His645fs)	Pathogenic
4686746	NM_000085.5(CLCNKB):c.1521_1529delinsT (p.Ala508fs)	Pathogenic
4688289	NM_000085.5(CLCNKB):c.1066C>T (p.Gln356Ter)	Pathogenic
497329	NM_000085.5(CLCNKB):c.1166G>A (p.Trp389Ter)	Pathogenic
585704	NM_000085.5(CLCNKB):c.18dup (p.Leu7fs)	Pathogenic
7595	NM_000085.5(CLCNKB):c.1294T>C (p.Tyr432His)	Pathogenic
7596	NC_000001.11:g.(?16043782)(16057326_?)del	Pathogenic
7598	NC_000001.11:g.(16034051_16043781)(16043881?)del	Pathogenic
801446	NM_000085.5(CLCNKB):c.673G>T (p.Glu225Ter)	Pathogenic
801447	NM_000085.5(CLCNKB):c.708C>A (p.Tyr236Ter)	Pathogenic
930786	NM_000085.5(CLCNKB):c.1389del (p.Tyr466fs)	Pathogenic

SpliceAI

3168 predictions. Top by Δscore:

Variant	Effect	Δscore
1:16043878:CAGG:C	donor_loss	1.0000
1:16043880:GGTG:G	donor_loss	1.0000
1:16043881:GTG:G	donor_loss	1.0000
1:16044482:CCAG:C	acceptor_loss	1.0000
1:16044483:CAG:C	acceptor_loss	1.0000
1:16044484:A:AG	acceptor_gain	1.0000
1:16044484:AG:A	acceptor_gain	1.0000
1:16044484:AGG:A	acceptor_gain	1.0000
1:16044484:AGGG:A	acceptor_gain	1.0000
1:16044485:G:A	acceptor_loss	1.0000
1:16044485:G:GG	acceptor_gain	1.0000
1:16044485:GG:G	acceptor_gain	1.0000
1:16044485:GGG:G	acceptor_gain	1.0000
1:16044485:GGGG:G	acceptor_gain	1.0000
1:16044485:GGGGC:G	acceptor_gain	1.0000
1:16044591:AGG:A	donor_loss	1.0000
1:16044592:GGTGA:G	donor_loss	1.0000
1:16044593:G:C	donor_loss	1.0000
1:16044594:T:G	donor_loss	1.0000
1:16045681:TCCG:T	donor_gain	1.0000
1:16048039:A:T	donor_gain	1.0000
1:16048042:GTG:G	donor_gain	1.0000
1:16048416:CTGAG:C	donor_loss	1.0000
1:16048418:GAGG:G	donor_loss	1.0000
1:16048419:AGGTT:A	donor_loss	1.0000
1:16048420:GGTT:G	donor_loss	1.0000
1:16048421:G:GC	donor_loss	1.0000
1:16048580:GCG:G	donor_gain	1.0000
1:16049164:T:A	acceptor_gain	1.0000
1:16049165:G:A	acceptor_gain	1.0000

AlphaMissense

4460 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:16051725:G:C	R438P	0.994
1:16052215:G:T	G476W	0.993
1:16048579:A:C	S218R	0.992
1:16048581:C:A	S218R	0.992
1:16048581:C:G	S218R	0.992
1:16051710:G:A	G433E	0.992
1:16051724:C:A	R438S	0.991
1:16052207:C:A	A473D	0.991
1:16049826:G:A	G293D	0.990
1:16051812:C:A	A467D	0.990
1:16051722:G:A	G437E	0.989
1:16052201:C:A	A471D	0.989
1:16049131:A:C	S223R	0.988
1:16049133:C:A	S223R	0.988
1:16049133:C:G	S223R	0.988
1:16049665:T:C	F277L	0.988
1:16049667:C:A	F277L	0.988
1:16049667:C:G	F277L	0.988
1:16050992:T:A	W391R	0.988
1:16050992:T:C	W391R	0.988
1:16052200:G:C	A471P	0.988
1:16052311:G:C	A508P	0.988
1:16051547:G:A	G433R	0.986
1:16051547:G:C	G433R	0.986
1:16051713:C:A	A434D	0.986
1:16052216:G:A	G476E	0.986
1:16046591:T:A	W96R	0.985
1:16046591:T:C	W96R	0.985
1:16051721:G:T	G437W	0.985
1:16048550:G:A	G208D	0.984

dbSNP variants (sampled 300 via entrez): RS1000239043 (1:16046045 C>A,T), RS1001135349 (1:16051102 G>A), RS1001577009 (1:16041785 G>A), RS1001836886 (1:16051645 T>C), RS1002342149 (1:16056171 A>T), RS1002522538 (1:16043113 A>G), RS1002969866 (1:16047986 A>T), RS1002984962 (1:16042798 T>C), RS1003018415 (1:16047731 T>C), RS1004325507 (1:16043439 C>T), RS1004377560 (1:16043182 C>T), RS1005193759 (1:16049303 C>G,T), RS1006548698 (1:16044674 C>A,T), RS1006646921 (1:16044881 A>G), RS1006909098 (1:16054123 T>G)

Disease associations

OMIM: gene MIM:602023 | disease phenotypes: MIM:613090, MIM:607364, MIM:601678, MIM:617184, MIM:607634, MIM:604364

GenCC curated gene-disease

Disease	Classification	Inheritance
Bartter disease type 3	Strong	Autosomal recessive
Bartter disease type 4B	Strong	Autosomal recessive
Gitelman syndrome	Supportive	Autosomal recessive
Bartter syndrome type 4	Supportive	Autosomal recessive

Mondo (9): Bartter disease type 4B (MONDO:0000909), Bartter disease type 3 (MONDO:0011822), Bartter syndrome (MONDO:0015231), mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant (MONDO:0014959), proteinuria (MONDO:0003634), autosomal dominant osteopetrosis 1 (MONDO:0011877), epilepsy, familial focal, with variable foci 1 (MONDO:0024556), Gitelman syndrome (MONDO:0009904), Bartter syndrome type 4 (MONDO:0019524)

Orphanet (3): Bartter syndrome (Orphanet:112), Bartter syndrome type 3 (Orphanet:93605), Autosomal dominant osteopetrosis type 1 (Orphanet:2783)

HPO phenotypes

125 total (30 of 125 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000017	Nocturia
HP:0000020	Urinary incontinence
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000103	Polyuria
HP:0000121	Nephrocalcinosis
HP:0000127	Renal salt wasting
HP:0000128	Renal potassium wasting
HP:0000325	Triangular face
HP:0000360	Tinnitus
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000591	Abnormal sclera morphology
HP:0000610	Abnormal choroid morphology
HP:0000622	Blurred vision
HP:0000712	Emotional lability
HP:0000805	Enuresis
HP:0000822	Hypertension
HP:0000823	Delayed puberty
HP:0000841	Hyperactive renin-angiotensin system
HP:0000848	Increased circulating renin concentration
HP:0000855	Insulin resistance
HP:0000859	Increased circulating aldosterone concentration
HP:0000872	Hashimoto thyroiditis
HP:0000934	Chondrocalcinosis
HP:0000969	Edema
HP:0000975	Hyperhidrosis
HP:0001249	Intellectual disability

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004601_2	Red blood cell count	1.000000e-09
GCST010083_69	Hemoglobin levels	2.000000e-08
GCST90002383_146	Hematocrit	4.000000e-23
GCST90002384_527	Hemoglobin	5.000000e-22
GCST90002403_33	Red blood cell count	5.000000e-20

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001477	Bartter Syndrome	C12.050.351.968.419.815.279; C12.200.777.419.815.279; C12.950.419.815.279; C19.053.800.604.249
D053579	Gitelman Syndrome	C12.050.351.968.419.815.491; C12.200.777.419.815.491; C12.950.419.815.491; C16.320.831.491
D011507	Proteinuria	C12.050.351.968.934.734; C12.200.777.934.734; C12.950.934.734; C23.888.942.750
C536056	Osteopetrosis autosomal dominant type 1 (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

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
niflumic acid	Activator	5.0	pEC50

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
entinostat	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
perfluorobutanesulfonic acid	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Catechin	affects cotreatment, increases expression	1
Methapyrilene	decreases methylation	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression	1
Zinc Sulfate	decreases expression	1
Magnetite Nanoparticles	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_F0RG	HHUUKDi014-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02297048	PHASE4	COMPLETED	Monocentric STUDY, Randomised Double Blinded (Healthy Subjects, or Transversal (Patients With Gitelman Syndrome)
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00369538	PHASE4	SUSPENDED	Specific Blockage of Angiotensine 2 and Podocyturia in Glomerular Nephropathies With Hypertension and Proteinuria
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00550095	PHASE4	COMPLETED	To Assess the Effects of Valsartan on Albuminuria/Proteinuria in Hypertensive Patients With Type 2 Diabetes Mellitus
NCT00674596	PHASE4	COMPLETED	The Effect of Renin Angiotensin System Blockage (RAS) Blockade On PTX3 Levels In Diabetic Patients With Proteinuria
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00921570	PHASE4	COMPLETED	The Effects of Renin Angiotensin System Blockage (RAS), Calcium Channel Blocker and Combined Drugs on TWEAK, PTX3 and FMD Levels in Diabetic Proteinuric Patients With Hypertension
NCT00961207	PHASE4	TERMINATED	Triple Blockade of the Renin Angiotensin Aldosterone System in Diabetic (Type 1&2) Proteinuric Patients
NCT01169857	PHASE4	WITHDRAWN	Velcade for Proliferative Lupus Nephritis
NCT01219413	PHASE4	COMPLETED	Influence of Aliskiren on Proteinuria
NCT01386554	PHASE4	COMPLETED	Acthar for Treatment of Proteinuria in Membranous Nephropathy Patients
NCT01512862	PHASE4	UNKNOWN	Anti-proteinuric Effect of Calcitriol in Non-diabetic Kidney Disease Patients
NCT01541267	PHASE4	COMPLETED	The Effect of Various Types of the Renin-angiotensin-aldosterone System Blockade on Proteinuria
NCT01637259	PHASE4	COMPLETED	MARCH Renal Substudy
NCT01703234	PHASE4	COMPLETED	FGF-23 and Endothelial Dysfunction in Diabetic Proteinuric Patients
NCT01820832	PHASE4	UNKNOWN	Oral Calcitriol for Reduction of Mild Proteinuria in Patients With CKD
NCT01827202	PHASE4	COMPLETED	RAS Quantification in Patients With Aliskiren or Candesartan
NCT02057523	PHASE4	TERMINATED	Acthar as Rescue Therapy for Transplant Glomerulopathy in Kidney Transplant Recipients
NCT02063100	PHASE4	UNKNOWN	Efficacy and Safety of Shenyankangfu Tablets for Primary Glomerulonephritis
NCT02382523	PHASE4	WITHDRAWN	Acthar on Proteinuria in IgA Nephropathy Patients
NCT02522650	PHASE4	UNKNOWN	A Crossover Pilot Study of the Effect of Amiloride on Proteinuria
NCT03195023	PHASE4	UNKNOWN	Effect of RAS Blockers on CKD Progression in Elderly Patients With Non Proteinuric Nephropathies (PROERCAN01)
NCT03550859	PHASE4	UNKNOWN	HMG-CoA Reductase add-on in Chronic Kidney Disease Patients With Proteinuria
NCT03983551	PHASE4	COMPLETED	Comparing the Renal Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas
NCT04531397	PHASE4	WITHDRAWN	Efficacy and Safety of Dapagliflozin in Children With Proteinuric Chronic Kidney Disease
NCT04534270	PHASE4	COMPLETED	Efficacy and Safety of Dapagliflozin in Children With Proteinuria
NCT06374043	PHASE4	COMPLETED	Decentralized N=1 Study: A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin.
NCT07030894	PHASE4	RECRUITING	Nefecon and Ambrisentan in IgA Nephropathy
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT07358520	PHASE4	NOT_YET_RECRUITING	Clinical Study on the Use of Huaier Granules for the Treatment of Proteinuria Related to Bevacizumab and Anlotinib in Lung Cancer Patients
NCT00141453	PHASE3	COMPLETED	ORIENT: Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial
NCT00199927	PHASE3	COMPLETED	Statins in Proteinuric Nephropathies
NCT00242346	PHASE3	COMPLETED	High Doses of Candesartan Cilexetil on the Reduction of Proteinuria
NCT00362960	PHASE3	COMPLETED	Olmesartan Medoxomil and Diabetic Nephropathy
NCT00507494	PHASE3	COMPLETED	Influence of Pioglitazone for Renal Transplant Function in Diabetics
NCT00568178	PHASE3	COMPLETED	An Extension Study Designed to Assess Effects of Losartan on Proteinuria in Pediatric Populations (MK-0954-326 AM1,EXT1(AM2))