CLCN3

Summary

CLCN3 (Cl-/H+ antiporter 3, HGNC:2021) is a protein-coding gene on chromosome 4q33, encoding H(+)/Cl(-) exchange transporter 3 (P51790). Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.

This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 1182 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 209 total — 3 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 98
• Druggable target: yes
• MANE Select transcript: NM_001829

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2021
Approved symbol	CLCN3
Name	Cl-/H+ antiporter 3
Location	4q33
Locus type	gene with protein product
Status	Approved
Aliases	CLC3, ClC-3
Ensembl gene	ENSG00000109572
Ensembl biotype	protein_coding
OMIM	600580
Entrez	1182

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000347613, ENST00000360642, ENST00000502998, ENST00000506924, ENST00000507875, ENST00000511092, ENST00000512813, ENST00000513761, ENST00000515420, ENST00000898874, ENST00000898875, ENST00000942633, ENST00000942634

RefSeq mRNA: 4 — MANE Select: NM_001829 NM_001243372, NM_001243374, NM_001829, NM_173872

CCDS: CCDS34100, CCDS34101, CCDS58932, CCDS75208

Canonical transcript exons

ENST00000513761 — 13 exons

Exon	Start	End
ENSE00000929983	169687658	169687757
ENSE00001081725	169689043	169689230
ENSE00001081726	169690530	169690652
ENSE00001151748	169697189	169697734
ENSE00001151761	169692114	169692320
ENSE00001221988	169680050	169680207
ENSE00002031755	169620578	169621063
ENSE00002041075	169719907	169723673
ENSE00002237024	169713079	169713295
ENSE00002240163	169703998	169704184
ENSE00002246524	169706868	169707266
ENSE00002270312	169695612	169695692
ENSE00003637550	169635913	169636088

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.1031 / max 1665.0193, expressed in 1820 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50564	29.8150	1811
50571	14.4152	1491
50567	2.3605	1039
50565	2.1908	1141
50570	2.1592	625
50563	1.6690	896
50566	0.7588	396
50568	0.4273	190
50569	0.1958	94
50562	0.1113	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	98.10	gold quality
endothelial cell	CL:0000115	98.04	gold quality
colonic mucosa	UBERON:0000317	97.71	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.10	gold quality
choroid plexus epithelium	UBERON:0003911	96.98	gold quality
pigmented layer of retina	UBERON:0001782	96.95	gold quality
postcentral gyrus	UBERON:0002581	96.90	gold quality
islet of Langerhans	UBERON:0000006	96.84	gold quality
adrenal tissue	UBERON:0018303	96.84	gold quality
parotid gland	UBERON:0001831	96.66	gold quality
parietal lobe	UBERON:0001872	96.61	gold quality
heart right ventricle	UBERON:0002080	96.59	gold quality
superior vestibular nucleus	UBERON:0007227	96.56	gold quality
CA1 field of hippocampus	UBERON:0003881	96.48	gold quality
tongue squamous epithelium	UBERON:0006919	96.42	gold quality
pons	UBERON:0000988	96.39	gold quality
medulla oblongata	UBERON:0001896	96.39	gold quality
corpus epididymis	UBERON:0004359	96.34	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.23	gold quality
medial globus pallidus	UBERON:0002477	96.19	gold quality
subthalamic nucleus	UBERON:0001906	96.18	gold quality
cranial nerve II	UBERON:0000941	96.13	gold quality
corpus callosum	UBERON:0002336	96.09	gold quality
inferior olivary complex	UBERON:0002127	95.97	gold quality
upper leg skin	UBERON:0004262	95.97	gold quality
globus pallidus	UBERON:0001875	95.88	gold quality
substantia nigra pars compacta	UBERON:0001965	95.85	gold quality
entorhinal cortex	UBERON:0002728	95.83	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.82	gold quality
ventricular zone	UBERON:0003053	95.75	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.78
E-MTAB-9467	no	0.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT3

miRNA regulators (miRDB)

231 targeting CLCN3, 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-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-302C-5P	99.97	72.56	3642

Literature-anchored findings (GeneRIF, showing 40)

• ClC-3 is an important molecular component underlying VSOACs and the RVD process in HeLa cells (PMID:12183454)
• results show that the ClC-3B PDZ-binding isoform resides in the Golgi where it co-localizes with a small amount of CFTR (cystic fibrosis transmembrane conductance regulator) (PMID:12471024)
• results suggest a fundamental role of endogenous ClC-3 in the swelling-activated Cl- channels function and cell volume regulation in human gastric epithelial cells (PMID:12842831)
• ClC-2 and ClC-3 channels are specifically upregulated in glioma membranes and endow glioma cells with an enhanced ability to transport Chloride (PMID:12843258)
• ClC-3 and ZnT3 reside in a common vesicle population where they functionally interact to determine vesicle luminal composition. (PMID:15073168)
• volume-regulated ClC-3 Cl(-) channels play important role in the regulation of Cl(-) and cell proliferation of vascular smooth muscle cells (PMID:15596438)
• Clcn3 was considered the most likely candidate of Cl- channel involved in volume regulation of human sperm. (PMID:16033995)
• ClC-3 is required for normal neutrophil oxidative function, phagocytosis, and transendothelial migration (PMID:16522634)
• This study demonstrates that superoxide flux across the endothelial cell plasma membrane occurs through chloride channel-3 channels and induces intracellular calcium release, which activates mitochondrial superoxide generation. (PMID:17360969)
• The relative density of CLC-3 mRNA was 0.22+/-0.09 and 0.12+/-0.05 in HNECs treated with 3 and 0.9% saline, respectively. (PMID:17869465)
• CLC-3 is upregulated in ethmoid mucosa and may affect the development of chronic rhinosinusitis without nasal polyps. (PMID:17882904)
• inhibition of the NADPH oxidase or ClC-3 in otherwise unstimulated cells elicited a phenotype similar to that seen after endotoxin priming, suggesting that basal oxidant production helps to maintain cellular quiescence. (PMID:17908687)
• oxidation induces surface expression of ClC-3 and activation of a ClC-3-dependent anion permeability in K562 cells (PMID:17976378)
• ClC-3 overexpression induced a pH-sensitive conductance in HEK293T cells that is biophysically similar to ClC-4 and ClC-5. (PMID:17977943)
• These data confirm that ClC-3 is important in VRAC function and cell volume regulation, is associated with the I(Cl,LPA) current activity, and participates in the fibroblast-to-myofibroblast transition. (PMID:18077605)
• An essential role of sClC-3 in native volume-sensitive outwardly rectifying anion channels function in mouse atrial myocytes. (PMID:18986326)
• CaMKII is a molecular link translating intracellular calcium changes, which are intrinsically associated with glioma migration, to changes in ClC-3 conductance required for cell movement (PMID:20139089)
• ClC-3 is involved in the activation of volume-activated chloride currents but not of stretch-activated chloride currents in hepatocellular carcinoma cells. (PMID:20945353)
• High ClC-3 is associated with extensive migration and invasion in glioma. (PMID:21115901)
• ClC-3 may be a main component of background chloride channels which can be activated under isotonic conditions by autocrine/paracrine ATP through purinergic receptor pathways; the background current is involved in maintenance of basal cell volume. (PMID:21792908)
• study demonstrates that premitotic condensation involves the activation of ClC-3 by Ca(2+)/calmodulin-dependent protein kinase II in glioma cells (PMID:22049206)
• ClC-3 protein may be considered as a potential tumor marker and therapeutic target for human nasopharyngeal carcinoma. (PMID:22108225)
• results reveal a cell cycle-dependent change of the subcellular distribution of ClC-3 and strongly suggest that ClC-3 has nucleocytoplasmic shuttling dynamics that may play key regulatory roles during different stages of the cell cycle in tumor cells. (PMID:22371056)
• ClC-3 is a candidate of the channel proteins that mediate or regulate the acid-activated chloride current in nasopharyngeal carcinoma cells. (PMID:22496242)
• Data indicate in umbilical vein endothelial cells transfected with ClC-3 siRNA showed activation of NF-kappaB. (PMID:23006728)
• our data suggest that the ClC-3 chloride channel is an important target of cyclin D1. Cyclin D1 may regulate the functional activities of the chloride channel via CDK4 and CDK6, and/or the expression of the chloride channel. (PMID:23270726)
• K(Ca)3.1 and ClC-3 are expressed in tissue samples obtained from patients diagnosed with grade IV gliomas. Both K(Ca)3.1 and ClC-3 colocalize to the invading processes of glioma cells (PMID:23345219)
• Suggest that ClC-3 suppression causes the inhibition of Akt and autophagy, which can enhance the therapeutic benefit of cisplatin in U251 cells. (PMID:23408563)
• ClC-3 deficiency inhibited Ang II-induced EPC apoptosis via suppressing ROS generation derived from NADPH oxidase. (PMID:23873092)
• swelling-activated Cl currents and CLC-3 play a role in pulmonary artery smooth muscle cell proliferation, but CLC-3 channels do not underlie swelling in these cells (PMID:24284495)
• Authors summarize the function of CLC-3 in cancer and discuss the mechanisms by which CLC-3 contributes to proliferation, apoptosis and drug resistance in cancer cells. [Review] (PMID:25421907)
• CLC3 is required in the activation and migration of human blood eosinophils. (PMID:25514499)
• Data indicate that cytoplasmic chloride channel-3 (ClC-3) plays an active and key role in tumor metastasis and may be a valuable prognostic biomarker and a therapeutic target to prevent tumor spread. (PMID:25537517)
• these results demonstrated that ClC-3 is involved in the proliferation and migration of osteosarcoma cell (PMID:25973047)
• ClC-3 promotes endometriotic cell migration and invasion. (PMID:26965430)
• Study provided novel and compelling evidence for the functional role of the unique CLC-3, which are significantly upregulated during ischemia, in the protection of the heart under stress (PMID:27064645)
• Transfection of cells with ClC-3 siRNA decreased the expression of cyclin D1, cyclin dependent kinase 4 and 6, and increased the expression of cyclin dependent kinase inhibitors (CDKIs), p21 and p27. Pretreatments of cells with p21 and p27 siRNAs depleted the inhibitory effects of ClC-3 siRNA on the expression of CDK4 and CDK6, but not on that of cyclin D1 (PMID:27451945)
• ClC-3 is a potential target of 17beta-estradiol and is modulated by the ERalpha in breast cancer cells. (PMID:28419445)
• Unique oligomerization properties of ClC-4 permit regulated targeting of ClC-4 to various endosomal compartment systems via expression of different ClC-3 splice variants. (PMID:28972156)
• we demonstrated that ClC-3 can arrest the cell cycle at the G1 phase to inhibit cell proliferation, suggesting that ClC-3 has the potential to be a novel target for hepatocellular carcinoma (HCC) therapy and potentially improve the prognosis of HCC patients (PMID:29749557)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	clcn3	ENSDARG00000003269
mus_musculus	Clcn3	ENSMUSG00000004319
rattus_norvegicus	Clcn3	ENSRNOG00000010682
drosophila_melanogaster	ClC-c	FBGN0036566
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN6 (ENSG00000011021), CLCN4 (ENSG00000073464), CLCN7 (ENSG00000103249), CLCN2 (ENSG00000114859), CLCN5 (ENSG00000171365), CLCNKB (ENSG00000184908), CLCNKA (ENSG00000186510), CLCN1 (ENSG00000188037)

Protein

Protein identifiers

H(+)/Cl(-) exchange transporter 3 — P51790 (reviewed: P51790)

Alternative names: Chloride channel protein 3, Chloride transporter ClC-3

All UniProt accessions (5): P51790, D6RDZ6, D6RIX3, E9PE15, H0Y8Z8

UniProt curated annotations — full annotation on UniProt →

Function. Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The presence of conserved gating glutamate residues is typical for family members that function as antiporters. Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.

Subunit / interactions. Monomer and homodimer. Forms heterodimers with CLCN4. Interacts with GOPC, PDZK1 and NHERF1/EBP50.

Subcellular location. Early endosome membrane. Late endosome membrane. Lysosome membrane. Cell membrane Golgi apparatus membrane. Cell projection. Ruffle membrane.

Tissue specificity. Expressed primarily in tissues derived from neuroectoderm. Within the brain, its expression is particularly evident in the hippocampus, olfactory cortex, and olfactory bulb. Highly expressed in aortic and coronary vascular smooth muscle cells, and aortic endothelial cells. Also expressed in tracheal and alveolar epithelial cells, and intima and media of the pulmonary vessels. Expressed in bronchus and colon (at protein level).

Post-translational modifications. N-glycosylated.

Disease relevance. Neurodevelopmental disorder with hypotonia and brain abnormalities (NEDHYBA) [MIM:619512] An autosomal dominant disorder characterized by onset in infancy or early childhood, global developmental delay, hypotonia, impaired intellectual development, and poor or absent speech. Additional variable manifestations may be present, including feeding difficulties, seizures, behavioral abnormalities, and non-specific dysmorphic facial features. Brain imaging shows variable abnormalities, including corpus callosum and cerebellar defects, and decreased white matter volume. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with seizures and brain abnormalities (NEDSBA) [MIM:619517] An autosomal recessive neurologic disorder characterized by global developmental delay and onset of seizures in the first months of life, and structural brain defects on brain imaging. Additional features may include pigmentary retinopathy with poor visual fixation and spasticity. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Isoform 2 contains a C-terminal PDZ-binding motif mediating the interaction with GOPC.

Similarity. Belongs to the chloride channel (TC 2.A.49) family. ClC-3/CLCN3 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P51790-1	1, ClC-3A	yes
P51790-2	2, ClC-3B
P51790-4	3
P51790-5	4

RefSeq proteins (4): NP_001230301, NP_001230303, NP_001820, NP_776297 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR001807	ClC	Family
IPR002245	ClC3	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily

Pfam: PF00571, PF00654

UniProt features (54 total): transmembrane region 10, sequence variant 8, intramembrane region 6, short sequence motif 6, binding site 5, sequence conflict 5, glycosylation site 3, splice variant 3, topological domain 2, domain 2, site 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9DO0	ELECTRON MICROSCOPY	2.54
9DNX	ELECTRON MICROSCOPY	2.86
9DNW	ELECTRON MICROSCOPY	2.9
9DNY	ELECTRON MICROSCOPY	3.01
9DNZ	ELECTRON MICROSCOPY	3.16

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51790-F1	79.95	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): 282 (mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking h(+) and cl(-) transport); 339 (mediates proton transfer from the protein to the inner aqueous phase)

Ligand- & substrate-binding residues (5): 239; 527; 630; 689–691; 796–799

Glycosylation sites (3): 177, 451, 479

Mutagenesis-validated functional residues (1):

Position	Phenotype
280	changes channel selectivity from i(-)>cl(-) to cl(-)>i(-).

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 625 (showing top): MORF_ITGA2, GCM_MAP4K4, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, GOBP_BEHAVIOR, GOBP_ENDOSOME_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_ADULT_BEHAVIOR, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_RUFFLE

GO Biological Process (16): regulation of pH (GO:0006885), phagocytosis, engulfment (GO:0006911), adult locomotory behavior (GO:0008344), synaptic transmission, glutamatergic (GO:0035249), photoreceptor cell maintenance (GO:0045494), negative regulation of cell volume (GO:0045794), endosomal lumen acidification (GO:0048388), synaptic transmission, GABAergic (GO:0051932), synaptic vesicle lumen acidification (GO:0097401), chloride transmembrane transport (GO:1902476), positive regulation of reactive oxygen species biosynthetic process (GO:1903428), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), transmembrane transport (GO:0055085), neuron cellular homeostasis (GO:0070050), proton transmembrane transport (GO:1902600)

GO Molecular Function (10): voltage-gated chloride channel activity (GO:0005247), chloride channel activity (GO:0005254), ATP binding (GO:0005524), antiporter activity (GO:0015297), PDZ domain binding (GO:0030165), chloride:proton antiporter activity (GO:0062158), volume-sensitive chloride channel activity (GO:0072320), nucleotide binding (GO:0000166), protein binding (GO:0005515), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (27): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), early endosome (GO:0005769), late endosome (GO:0005770), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), endosome membrane (GO:0010008), vesicle membrane (GO:0012506), membrane (GO:0016020), secretory granule (GO:0030141), synaptic vesicle membrane (GO:0030672), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), ruffle membrane (GO:0032587), specific granule (GO:0042581), axon terminus (GO:0043679), phagocytic vesicle (GO:0045335), recycling endosome (GO:0055037), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), lysosome (GO:0005764), endosome (GO:0005768), cell projection (GO:0042995)

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
endosome	3
chemical synaptic transmission	2
transport	2
chloride channel activity	2
chloride transmembrane transporter activity	2
bounding membrane of organelle	2
cytoplasm	2
endomembrane system	2
presynapse	2
cellular anatomical structure	2
endosome membrane	2
monoatomic cation homeostasis	1
biological regulation	1
phagocytosis	1
plasma membrane invagination	1
locomotory behavior	1
adult behavior	1
retina homeostasis	1
multicellular organismal process	1
cell volume homeostasis	1
endosome organization	1
intracellular pH reduction	1
intercellular transport	1
synaptic vesicle maturation	1
establishment of localization in cell	1
neuron cellular homeostasis	1
synaptic vesicle cycle	1
proton transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
positive regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species biosynthetic process	1
positive regulation of reactive oxygen species metabolic process	1
monoatomic anion transport	1
inorganic anion transport	1
cellular process	1
cellular homeostasis	1
monoatomic cation transmembrane transport	1
voltage-gated monoatomic anion channel activity	1

Protein interactions and networks

STRING

1475 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCN3	MMP2	P08253	863
CLCN3	GPM6A	P51674	838
CLCN3	ATP5MC2	Q06055	772
CLCN3	ATP5MC3	P48201	765
CLCN3	OSTM1	Q86WC4	738
CLCN3	ATP5MC1	P05496	732
CLCN3	BEST1	O76090	676
CLCN3	LRRC8A	Q8IWT6	621
CLCN3	CFTR	P13569	591
CLCN3	ANO1	Q5XXA6	584
CLCN3	ARHGEF1	Q92888	576
CLCN3	PPT1	P50897	547
CLCN3	LRRC8D	Q7L1W4	547
CLCN3	LRRC8B	Q6P9F7	541
CLCN3	CLCA1	A8K7I4	533

IntAct

64 interactions, top by confidence:

A	B	Type	Score
TMEM9B	DNAJC13	psi-mi:“MI:0914”(association)	0.640
GGA1	CLCN3	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
TPCN2	AP3B1	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
KLHL10	PXDNL	psi-mi:“MI:0914”(association)	0.530
CLCN3	CHCHD3	psi-mi:“MI:0915”(physical association)	0.400
CLCN3	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
MOGAT2	CLCN3	psi-mi:“MI:0915”(physical association)	0.400
HSPB1	CLCN3	psi-mi:“MI:0915”(physical association)	0.370
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
TPCN2	DDX11L8	psi-mi:“MI:0914”(association)	0.350
LGALS9	PODXL	psi-mi:“MI:0914”(association)	0.350
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.350
SCAMP1	SCAMP3	psi-mi:“MI:0914”(association)	0.350
AVPR2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
GGA1	RABGAP1L	psi-mi:“MI:0914”(association)	0.350
KCNE3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
OR10H2	ABCD4	psi-mi:“MI:0914”(association)	0.350
LYPD3	TNPO2	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
OR4N2	EMC8	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

BioGRID (93): CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Two-hybrid), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), CLCN3 (Affinity Capture-RNA), CLCN3 (Affinity Capture-MS), DNAJC5 (FRET), CLCN3 (Affinity Capture-RNA)

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, P60300, P92941, P92942

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CLCN3	“down-regulates quantity”	chloride	relocalization
CAMK2A	“up-regulates activity”	CLCN3	phosphorylation
TFE3	“up-regulates quantity by expression”	CLCN3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	13
Uncertain significance	160
Likely benign	16
Benign	2

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1192292	NM_001829.4(CLCN3):c.336_339del (p.Lys112fs)	Pathogenic
2571618	NM_001829.4(CLCN3):c.2033A>C (p.Asp678Ala)	Pathogenic
4813604	NM_001829.4(CLCN3):c.925A>G (p.Lys309Glu)	Pathogenic
1192286	NM_001829.4(CLCN3):c.254A>G (p.Tyr85Cys)	Likely pathogenic
1192287	NM_001829.4(CLCN3):c.1357A>C (p.Ser453Arg)	Likely pathogenic
1192288	NM_001829.4(CLCN3):c.971T>C (p.Val324Ala)	Likely pathogenic
1192290	NM_001829.4(CLCN3):c.1820T>C (p.Ile607Thr)	Likely pathogenic
1192291	NM_001829.4(CLCN3):c.2315T>C (p.Val772Ala)	Likely pathogenic
2104448	NM_001829.4(CLCN3):c.1540A>T (p.Thr514Ser)	Likely pathogenic
2574683	NM_001829.4(CLCN3):c.1819A>G (p.Ile607Val)	Likely pathogenic
3778671	NM_001829.4(CLCN3):c.1312A>T (p.Thr438Ser)	Likely pathogenic
3901102	NM_001829.4(CLCN3):c.260A>T (p.Asp87Val)	Likely pathogenic
3910589	NM_001829.4(CLCN3):c.1075G>A (p.Ala359Thr)	Likely pathogenic
929948	NM_001829.4(CLCN3):c.1709C>T (p.Thr570Ile)	Likely pathogenic
986034	NM_001829.4(CLCN3):c.1358G>T (p.Ser453Ile)	Likely pathogenic
995566	NM_001829.4(CLCN3):c.755T>C (p.Ile252Thr)	Likely pathogenic

SpliceAI

3703 predictions. Top by Δscore:

Variant	Effect	Δscore
4:169620675:A:T	donor_gain	1.0000
4:169635909:ACAG:A	acceptor_loss	1.0000
4:169635910:CA:C	acceptor_loss	1.0000
4:169635911:A:AG	acceptor_gain	1.0000
4:169635911:AGA:A	acceptor_loss	1.0000
4:169635912:G:GA	acceptor_gain	1.0000
4:169635912:GAT:G	acceptor_gain	1.0000
4:169635912:GATA:G	acceptor_gain	1.0000
4:169635912:GATAA:G	acceptor_gain	1.0000
4:169636085:GTTG:G	donor_gain	1.0000
4:169636088:GGTAA:G	donor_loss	1.0000
4:169636089:G:GG	donor_gain	1.0000
4:169636089:G:T	donor_loss	1.0000
4:169636090:T:G	donor_loss	1.0000
4:169680044:CTGTA:C	acceptor_loss	1.0000
4:169680045:TGTA:T	acceptor_loss	1.0000
4:169680046:GTAG:G	acceptor_loss	1.0000
4:169680048:A:AG	acceptor_gain	1.0000
4:169680048:A:T	acceptor_loss	1.0000
4:169680048:AG:A	acceptor_gain	1.0000
4:169680049:G:GA	acceptor_gain	1.0000
4:169680049:GG:G	acceptor_gain	1.0000
4:169680049:GGA:G	acceptor_gain	1.0000
4:169680049:GGAA:G	acceptor_gain	1.0000
4:169680203:GACGG:G	donor_gain	1.0000
4:169680205:CGGGT:C	donor_loss	1.0000
4:169680206:GG:G	donor_gain	1.0000
4:169680206:GGGTA:G	donor_loss	1.0000
4:169680207:GG:G	donor_gain	1.0000
4:169680207:GGT:G	donor_loss	1.0000

AlphaMissense

5374 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:169680151:T:C	F88L	1.000
4:169680153:C:A	F88L	1.000
4:169680153:C:G	F88L	1.000
4:169680161:T:A	I91N	1.000
4:169680163:G:C	D92H	1.000
4:169680164:A:C	D92A	1.000
4:169680164:A:G	D92G	1.000
4:169680164:A:T	D92V	1.000
4:169680166:T:A	W93R	1.000
4:169680166:T:C	W93R	1.000
4:169680167:G:C	W93S	1.000
4:169680168:G:C	W93C	1.000
4:169680168:G:T	W93C	1.000
4:169680176:A:T	E96V	1.000
4:169687724:T:A	W129R	1.000
4:169687724:T:C	W129R	1.000
4:169687745:G:A	G136R	1.000
4:169687745:G:C	G136R	1.000
4:169687746:G:A	G136E	1.000
4:169687757:G:T	G140W	1.000
4:169689043:G:A	G140E	1.000
4:169689099:G:T	G159C	1.000
4:169689107:C:G	C161W	1.000
4:169689194:G:C	W190C	1.000
4:169689194:G:T	W190C	1.000
4:169690630:C:A	A236D	1.000
4:169690641:G:A	G240R	1.000
4:169690641:G:C	G240R	1.000
4:169690642:G:A	G240E	1.000
4:169690642:G:T	G240V	1.000

dbSNP variants (sampled 300 via entrez): RS1000053848 (4:169656737 G>A), RS1000054081 (4:169630515 C>A), RS10000743 (4:169673044 T>A,C,G), RS1000090780 (4:169633773 T>C,G), RS1000182404 (4:169659935 T>G), RS10002133 (4:169642582 G>A,T), RS1000214247 (4:169619628 G>C), RS1000245635 (4:169687255 C>A,G,T), RS1000248242 (4:169668980 G>A,C,T), RS1000319542 (4:169687076 A>G,T), RS1000319962 (4:169643872 AT>A,ATT), RS1000346415 (4:169718916 T>G), RS1000357009 (4:169705844 G>A), RS1000408070 (4:169706120 C>T), RS1000427983 (4:169693582 T>A,C)

Disease associations

OMIM: gene MIM:600580 | disease phenotypes: MIM:619512, MIM:619517, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia and brain abnormalities	Strong	Autosomal dominant
complex neurodevelopmental disorder	Strong	Autosomal dominant
neurodevelopmental disorder with seizures and brain abnormalities	Limited	Autosomal recessive

Mondo (6): neurodevelopmental disorder with hypotonia and brain abnormalities (MONDO:0859187), neurodevelopmental disorder with seizures and brain abnormalities (MONDO:0859188), breast ductal adenocarcinoma (MONDO:0005590), autism, susceptiblity to (MONDO:0020836), complex neurodevelopmental disorder (MONDO:0100038), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Non-specific syndromic intellectual disability (Orphanet:528084)

HPO phenotypes

98 total (30 of 98 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000239	Large fontanelles
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000294	Low anterior hairline
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000418	Narrow nasal ridge
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000540	Hypermetropia
HP:0000556	Retinal dystrophy

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002539_54	Schizophrenia	1.000000e-09
GCST004521_54	Autism spectrum disorder or schizophrenia	9.000000e-09
GCST004946_50	Schizophrenia	7.000000e-11
GCST006803_41	Schizophrenia	3.000000e-08
GCST007201_292	Schizophrenia	1.000000e-07
GCST007201_469	Schizophrenia	1.000000e-08
GCST009325_32	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-10

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2401603 (SINGLE PROTEIN)

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
phloretin	Channel blocker	4.5	pIC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases methylation, increases expression	3
Cyclosporine	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	decreases expression	2
Chlorides	increases transport	2
Ozone	affects cotreatment, increases oxidation, increases abundance, decreases reaction, increases expression	2
Valproic Acid	affects expression, increases expression	2
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	increases abundance, increases expression	1
gluconic acid	increases response to substance	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
5-nitro-2-(3-phenylpropylamino)benzoic acid	increases expression, decreases response to substance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2405217	Binding	Activation of ClC-3 in human CNE2Z cells assessed as increase in chloride current in outward and inward direction at +80mV holding potential at 1 uM by whole-cell patch clamp method	Discovery of bufadienolides as a novel class of ClC-3 chloride channel activators with antitumor activities. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial