CLCN2

Summary

CLCN2 (chloride voltage-gated channel 2, HGNC:2020) is a protein-coding gene on chromosome 3q27.1, encoding Chloride channel protein 2 (P51788). Voltage-gated and osmosensitive chloride channel.

This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1181 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukoencephalopathy with mild cerebellar ataxia and white matter edema (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 706 total — 24 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• MANE Select transcript: NM_004366

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2020
Approved symbol	CLCN2
Name	chloride voltage-gated channel 2
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	CLC2, EJM6, ClC-2
Ensembl gene	ENSG00000114859
Ensembl biotype	protein_coding
OMIM	600570
Entrez	1181

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 17 protein_coding, 9 nonsense_mediated_decay, 6 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000265593, ENST00000344937, ENST00000430397, ENST00000434054, ENST00000457512, ENST00000465231, ENST00000475279, ENST00000485667, ENST00000491162, ENST00000636180, ENST00000636241, ENST00000636419, ENST00000636492, ENST00000636658, ENST00000636661, ENST00000636830, ENST00000636860, ENST00000637258, ENST00000637392, ENST00000637538, ENST00000637909, ENST00000638134, ENST00000881267, ENST00000881268, ENST00000881269, ENST00000881270, ENST00000881271, ENST00000881272, ENST00000881273, ENST00000938001, ENST00000962391, ENST00000962392, ENST00000962393

RefSeq mRNA: 4 — MANE Select: NM_004366 NM_001171087, NM_001171088, NM_001171089, NM_004366

CCDS: CCDS3263, CCDS54690, CCDS54691, CCDS54692

Canonical transcript exons

ENST00000265593 — 24 exons

Exon	Start	End
ENSE00001601396	184355374	184355529
ENSE00001729249	184354548	184354658
ENSE00001772945	184354904	184354973
ENSE00001898057	184346185	184346800
ENSE00001912027	184361417	184361605
ENSE00003465814	184353662	184353795
ENSE00003504438	184357182	184357266
ENSE00003504843	184352737	184352810
ENSE00003510424	184357779	184357856
ENSE00003524773	184357620	184357698
ENSE00003534233	184356993	184357094
ENSE00003537641	184355694	184355778
ENSE00003557626	184353250	184353422
ENSE00003569513	184358975	184359131
ENSE00003596294	184357962	184358095
ENSE00003606911	184352293	184352331
ENSE00003607159	184358682	184358813
ENSE00003609144	184357362	184357487
ENSE00003633027	184354101	184354314
ENSE00003661825	184353033	184353147
ENSE00003662667	184346935	184347021
ENSE00003673907	184358182	184358310
ENSE00003679041	184352443	184352496
ENSE00003694055	184352013	184352117

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 91.70.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4450 / max 62.7453, expressed in 608 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45887	1.4450	608

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	91.70	gold quality
tibial nerve	UBERON:0001323	89.96	gold quality
sural nerve	UBERON:0015488	89.09	gold quality
right testis	UBERON:0004534	88.76	gold quality
left testis	UBERON:0004533	88.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.06	gold quality
cerebellar hemisphere	UBERON:0002245	86.47	gold quality
transverse colon	UBERON:0001157	86.36	gold quality
cerebellar cortex	UBERON:0002129	86.24	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.99	gold quality
testis	UBERON:0000473	84.94	gold quality
rectum	UBERON:0001052	84.32	gold quality
cerebellum	UBERON:0002037	84.26	gold quality
gall bladder	UBERON:0002110	84.14	gold quality
right ovary	UBERON:0002118	83.41	gold quality
spinal cord	UBERON:0002240	82.40	gold quality
left ovary	UBERON:0002119	81.98	gold quality
left adrenal gland cortex	UBERON:0035825	81.82	gold quality
right adrenal gland	UBERON:0001233	81.37	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.35	gold quality
left adrenal gland	UBERON:0001234	81.13	gold quality
metanephros cortex	UBERON:0010533	80.97	gold quality
right adrenal gland cortex	UBERON:0035827	80.76	gold quality
right frontal lobe	UBERON:0002810	80.60	gold quality
ganglionic eminence	UBERON:0004023	80.48	gold quality
small intestine	UBERON:0002108	80.10	gold quality
colon	UBERON:0001155	80.04	gold quality
adrenal cortex	UBERON:0001235	80.04	gold quality
ventricular zone	UBERON:0003053	79.94	gold quality
pigmented layer of retina	UBERON:0001782	79.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ENAD-17	no	283.78
E-ANND-3	no	3.09

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3

miRNA regulators (miRDB)

41 targeting CLCN2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-6511A-5P	98.13	67.47	1770

Literature-anchored findings (GeneRIF, showing 40)

• found significant expression of ClC-2 at the apex of ciliated cells in both rat and human airways (PMID:11880269)
• a functional interaction between the ClC-2 chloride channel and the retrograde motor dynein complex. (PMID:12601004)
• 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)
• activation of hClC-2 is differentially regulated by PKA at two sites (PMID:15010473)
• Functional evaluation of mutated channels associated with idiopathic generalized epilepsies (PMID:15252188)
• activation of host ClC-2 channels participates in the altered permeability of Plasmodium-infected erythrocytes but is not required for intraerythrocytic parasite survival (PMID:15272009)
• These results indicate that ClC-2 may not be a Cl- -transporting protein for gastric acid secretion in parietal cells. (PMID:15388342)
• These data suggest that interferon-gamma activates ClC-2 channel activity in lung epithelial cells via mRNA stabilization. (PMID:15464978)
• The authors conclude that CLCN2 mutations may be a rare cause of familial epilepsy. Further studies are needed to test if polymorphisms in this gene are associated with epilepsy. (PMID:15505175)
• CLC-2 is not a key modifier gene of Cystic fibrosis lung disease phenotype. (PMID:15507145)
• CLCN2 is related to idiopathic generalized epilepsy. (PMID:15508929)
• FHII is linked to the chromosome 7p22 region but also shows predicted heterogeneity. (PMID:16003173)
• association of Hsp90 with ClC-2 results in greater channel activity due to increased cell surface channel expression, facilitation of channel opening, and enhanced channel sensitivity to intracellular [Cl-] (PMID:16049054)
• This suggests that slow and fast gating in ClC-2 are coupled, perhaps with slow gating contributing to the operation of the pore E207 as a protopore gate. (PMID:16469788)
• mutations in the CLCN2 gene are only a rare cause of idiopathic generalized epilepsy (PMID:16932951)
• CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy (PMID:17580110)
• Africans’ gene pool comprises CLCN2 gene variants in the N-terminus, the C-terminus or the pore domain that affect surface expression and voltage- or cell-swelling-stimulated channel gating (PMID:17762171)
• CLC-2 is upregulated in ethmoid mucosa and may affect the development of chronic rhinosinusitis without nasal polyps. (PMID:17882904)
• propose that the function of the ClC-2 carboxy-terminus is to slow down the time course of channel activation in order to stabilize neuronal excitability (PMID:18801843)
• Finding predicts a loss of function that may contribute to intracellular chloride accumulation or neuronal hyperexcitability. (PMID:19191339)
• two novel CLCN2 missense mutations, p.Arg235Gln and p.Arg577Gln, accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. (PMID:19191339)
• PIKfyve is a potent stimulator of ClC-2-activity and contributes to SGK1-dependent regulation of ClC-2. (PMID:19232516)
• GaTx2 specifically inhibits ClC-2 channels, showing no inhibitory effect on a battery of other major classes of chloride channels and voltage-gated potassium channels. GaTx2 is the first peptide toxin inhibitor of any ClC protein. (PMID:19574231)
• CLCN2 variants in indiopathic generalized epilepsy are reported. (PMID:19710712)
• ClC-2 requires residing in beta-cyclodextrin sensitive plasma membrane clusters with other molecules in order to remain active. Regulation of ClC-2 trafficking to (endocytic pathway) and within the membrane could be a means of modulating its activity. (PMID:19711355)
• Sequence analysis of CLCN2 at genomic DNA and cDNA levels in 18 megalencephalic leukoencephalopathy MLC1 mutations revealed some nucleotide changes, but they were predicted to be nonpathogenic. (PMID:20187760)
• ClC-2 plays an important role in the modulation of tight junctions by influencing caveolar trafficking of tight junction protein occludin. (PMID:21956164)
• This study demonistrated that the first auxiliary subunit of ClC-2 and suggests that ClC-2 may play a role in the pathology of MLC disease. (PMID:22405205)
• JAK2 down-regulates ClC-2 activity and thus counteracts Cl(-) exit, an effect which may impact on cell volume regulation (PMID:22613974)
• Our observations substantiate the concept that ClC-2 is involved in brain ion and water homoeostasis (PMID:23707145)
• Correlation between CLC-2 gene expression and the cytoskeleton in human trabecular meshwork cells. (PMID:23934342)
• SPAK and OSR1 are powerful negative regulators of the cell volume regulatory Cl- channel ClC-2 (PMID:25323061)
• both ubiquitous (AP-1A) and epithelium-specific (AP-1B) forms of the tetrameric clathrin adaptor AP-1 are capable of carrying out basolateral sorting of ClC-2. (PMID:25739457)
• The extracellular domain of GlialCAM is necessary for cell junction targeting and for mediating interactions with itself or with MLC1 and ClC-2. (PMID:26033718)
• Hyperpolarization activates CLC-2 mainly by driving intracellular anions into the channel pores. (PMID:26666914)
• The findings show that RGET691 of human ClC-2 (possible binding site) plays an important functional role in fatty acid activation of human ClC-2. (PMID:28424169)
• Leukoencephalopathy-causing CLCN2 mutations impair chloride channel gating and trafficking. (PMID:28905383)
• A role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. The mutations are the cause of a substantial fraction of early-onset primary aldosteronism. (PMID:29403011)
• CLCN2 mutations cause primary aldosteronism, this highlight the importance of chloride in aldosterone biosynthesis and CLCN2 as the foremost chloride conductor of resting glomerulosa cells. (PMID:29403012)
• ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin. (PMID:29550812)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	clcn2c	ENSDARG00000060439
danio_rerio	clcn2a	ENSDARG00000062427
		ENSDARG00000104550
mus_musculus	Clcn2	ENSMUSG00000022843
rattus_norvegicus	Clcn2	ENSRNOG00000001742
drosophila_melanogaster	ClC-c	FBGN0036566
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN6 (ENSG00000011021), CLCN4 (ENSG00000073464), CLCN7 (ENSG00000103249), CLCN3 (ENSG00000109572), CLCN5 (ENSG00000171365), CLCNKB (ENSG00000184908), CLCNKA (ENSG00000186510), CLCN1 (ENSG00000188037)

Protein

Protein identifiers

Chloride channel protein 2 — P51788 (reviewed: P51788)

All UniProt accessions (11): P51788, A0A1B0GTJ3, A0A1B0GTY0, A0A1B0GUY6, A0A1B0GUZ8, A0A1B0GV52, A0A1B0GVL9, A0A1B0GVU4, A0A1B0GVW7, A0A1B0GWC8, H7C0Q8

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated and osmosensitive chloride channel. Forms a homodimeric channel where each subunit has its own ion conduction pathway. Conducts double-barreled currents controlled by two types of gates, two fast glutamate gates that control each subunit independently and a slow common gate that opens and shuts off both subunits simultaneously. Displays inward rectification currents activated upon membrane hyperpolarization and extracellular hypotonicity. Contributes to chloride conductance involved in neuron excitability. In hippocampal neurons, generates a significant part of resting membrane conductance and provides an additional chloride efflux pathway to prevent chloride accumulation in dendrites upon GABA receptor activation. In glia, associates with the auxiliary subunit HEPACAM/GlialCAM at astrocytic processes and myelinated fiber tracts where it may regulate transcellular chloride flux buffering extracellular chloride and potassium concentrations. Regulates aldosterone production in adrenal glands. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated calcium channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Contributes to chloride conductance in retinal pigment epithelium involved in phagocytosis of shed photoreceptor outer segments and photoreceptor renewal. Conducts chloride currents at the basolateral membrane of epithelial cells with a role in chloride reabsorption rather than secretion. Permeable to small monovalent anions with chloride > thiocyanate > bromide > nitrate > iodide ion selectivity.

Subunit / interactions. Homodimer. Interacts with auxiliary subunit HEPACAM.

Subcellular location. Cell membrane. Basolateral cell membrane. Cell projection. Dendritic spine membrane. Axon.

Tissue specificity. Ubiquitously expressed. Moderately expressed in aortic and coronary vascular smooth muscle cells and expressed at a low level in aortic endothelial cells. Expressed in the adrenal gland, predominantly in the zona glomerulosa. Expressed in white mater perivascular astrocytes and ependymal cells (at protein level).

Post-translational modifications. Phosphorylated. Activated by dephosphorylation.

Disease relevance. Epilepsy, idiopathic generalized 11 (EIG11) [MIM:607628] A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Disease susceptibility is associated with variants affecting the gene represented in this entry. Juvenile absence epilepsy 2 (JAE2) [MIM:607628] A subtype of idiopathic generalized epilepsy characterized by onset occurring around puberty, absence seizures, generalized tonic-clonic seizures (GTCS), GTCS on awakening, and myoclonic seizures. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Juvenile myoclonic epilepsy 8 (EJM8) [MIM:607628] A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. Disease susceptibility is associated with variants affecting the gene represented in this entry. Leukoencephalopathy with ataxia (LKPAT) [MIM:615651] An autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles, suggesting myelin microvacuolation. Clinical features include ataxia and unstable gait. More variable abnormalities may include visual field defects, headaches, and learning disabilities. The disease is caused by variants affecting the gene represented in this entry. Hyperaldosteronism, familial, 2 (HALD2) [MIM:605635] An autosomal dominant disorder characterized by elevated plasma aldosterone level and hypertension of varying severity even within members of the same family. Hypokalemia is observed in some patients. In HALD2, hypertension does not improve with glucocorticoid treatment. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Common gate kinetics are down-regulated by intracellular ATP. Inhibited by AK-42, a derivative of meclofenamate. Inhibited by Cd(2+). Inhibited by Zn(2+) and PKC activation. Inhibited at acidic pH. CCLN2:HEPACAM channel conductance is up-regulated upon hypo-osmolarity.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the chloride channel (TC 2.A.49) family. ClC-2/CLCN2 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
P51788-1	1	yes
P51788-2	2
P51788-3	3
P51788-4	4
P51788-5	5

RefSeq proteins (4): NP_001164558, NP_001164559, NP_001164560, NP_004357* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001807	ClC	Family
IPR002244	Cl-channel-2	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily
IPR050970	Cl_channel_volt-gated	Family

Pfam: PF00654

Catalyzed reactions (Rhea), 5 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• nitrate(in) = nitrate(out) (RHEA:34923)
• iodide(out) = iodide(in) (RHEA:66324)
• thiocyanate(in) = thiocyanate(out) (RHEA:75347)
• bromide(in) = bromide(out) (RHEA:75383)

UniProt features (129 total): helix 30, sequence variant 24, strand 15, transmembrane region 10, turn 7, intramembrane region 7, splice variant 6, region of interest 5, short sequence motif 4, modified residue 4, binding site 3, mutagenesis site 3, topological domain 2, domain 2, site 2, sequence conflict 2, initiator methionine 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8TA3	ELECTRON MICROSCOPY	2.46
8TA2	ELECTRON MICROSCOPY	2.74
8TA4	ELECTRON MICROSCOPY	2.75
8TA5	ELECTRON MICROSCOPY	2.76
7XJA	ELECTRON MICROSCOPY	3.5
8GQU	ELECTRON MICROSCOPY	3.5
7XF5	ELECTRON MICROSCOPY	3.9
8TA6	ELECTRON MICROSCOPY	4.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51788-F1	72.82	0.34

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): 205 (protopore gate); 530 (couples extracellular acidification to the channel closure)

Ligand- & substrate-binding residues (3): 162; 459; 553

Post-translational modifications (4): 2, 20, 712, 758

Mutagenesis-validated functional residues (3):

Position	Phenotype
14–28	results in larger currents, faster activation kinetics and less rectification.
812	missorted to apical membrane of epithelial cells; when associated with a-813.
813	missorted to apical membrane of epithelial cells; when associated with a-812.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 333 (showing top): CREL_01, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_SALIVARY_GLAND_DEVELOPMENT, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_GLIAL_CELL_DIFFERENTIATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_MEMBRANE_DEPOLARIZATION, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (18): chloride transport (GO:0006821), phagocytosis, engulfment (GO:0006911), stabilization of membrane potential (GO:0030322), lung development (GO:0030324), regulation of aldosterone biosynthetic process (GO:0032347), positive regulation of oligodendrocyte differentiation (GO:0048714), retina development in camera-type eye (GO:0060041), regulation of resting membrane potential (GO:0060075), cell differentiation involved in salivary gland development (GO:0060689), cellular hypotonic response (GO:0071476), acinar cell differentiation (GO:0090425), regulation of membrane depolarization during action potential (GO:0098902), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), regulation of biological quality (GO:0065008), monoatomic anion transmembrane transport (GO:0098656), chloride transmembrane transport (GO:1902476)

GO Molecular Function (7): voltage-gated chloride channel activity (GO:0005247), chloride channel regulator activity (GO:0017081), volume-sensitive chloride channel activity (GO:0072320), chloride channel activity (GO:0005254), protein binding (GO:0005515), voltage-gated monoatomic anion channel activity (GO:0008308), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (15): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), dendritic spine membrane (GO:0032591), chloride channel complex (GO:0034707), axon initial segment (GO:0043194), perikaryon (GO:0043204), myelin sheath (GO:0043209), astrocyte end-foot (GO:0097450), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

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	5
chloride channel activity	3
monoatomic anion transport	2
regulation of membrane potential	2
transport	2
monoatomic anion channel activity	2
synaptic membrane	2
neuron projection	2
inorganic anion transport	1
phagocytosis	1
plasma membrane invagination	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
regulation of ketone biosynthetic process	1
aldosterone biosynthetic process	1
regulation of aldosterone metabolic process	1
regulation of steroid hormone biosynthetic process	1
regulation of alcohol biosynthetic process	1
positive regulation of glial cell differentiation	1
oligodendrocyte differentiation	1
regulation of oligodendrocyte differentiation	1
camera-type eye development	1
anatomical structure development	1
salivary gland development	1
cell differentiation	1
hypotonic response	1
cellular response to osmotic stress	1
glandular epithelial cell differentiation	1
regulation of membrane depolarization	1
membrane depolarization during action potential	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
biological regulation	1
monoatomic ion transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
voltage-gated monoatomic anion channel activity	1
ion channel regulator activity	1

Protein interactions and networks

STRING

1177 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCN2	EFHC1	Q5JVL4	922
CLCN2	CACNA1H	O95180	895
CLCN2	GABRG2	P18507	892
CLCN2	GABRA1	P14867	877
CLCN2	CACNB4	O00305	800
CLCN2	KCNMB3	Q9NPA1	795
CLCN2	GABRD	O14764	775
CLCN2	SCN1A	P35498	716
CLCN2	SCN1B	Q07699	709
CLCN2	GABRB3	P28472	686
CLCN2	ATP2B3	Q16720	634
CLCN2	KCNJ5	P48544	630
CLCN2	GABRA6	Q16445	619
CLCN2	HEPACAM	Q14CZ8	604
CLCN2	ATP1A1	P05023	598

IntAct

22 interactions, top by confidence:

A	B	Type	Score
CLCN2	MYH9	psi-mi:“MI:0915”(physical association)	0.400
MLF1	CLCN2	psi-mi:“MI:0915”(physical association)	0.400
CLCN2	Hacd3	psi-mi:“MI:0915”(physical association)	0.400
CLCN2		psi-mi:“MI:0915”(physical association)	0.400
BAG2	CLCN2	psi-mi:“MI:0915”(physical association)	0.400
NUDCD3	CLCN2	psi-mi:“MI:0915”(physical association)	0.400
PSMD2	CLCN2	psi-mi:“MI:0915”(physical association)	0.400
SGTA	CLCN2	psi-mi:“MI:0915”(physical association)	0.400
Usp19	CLCN2	psi-mi:“MI:0915”(physical association)	0.400
	CLCN2	psi-mi:“MI:0915”(physical association)	0.400
CLCN2	STUB1	psi-mi:“MI:0915”(physical association)	0.400
CLCN2	AARSD1	psi-mi:“MI:0915”(physical association)	0.400
CLCN2	PPP1CA	psi-mi:“MI:0915”(physical association)	0.370
CLCN2	ATXN1	psi-mi:“MI:0915”(physical association)	0.370
CLCN2	PEX10	psi-mi:“MI:0914”(association)	0.350
SEC62	GPR89A	psi-mi:“MI:0914”(association)	0.350
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350
AQP3	UBXN8	psi-mi:“MI:0914”(association)	0.350
CLCN2	JCHAIN	psi-mi:“MI:0914”(association)	0.350
SEC62	IPO8	psi-mi:“MI:0914”(association)	0.350

BioGRID (51): EIF4G1 (Affinity Capture-MS), NVL (Affinity Capture-MS), PEX10 (Affinity Capture-MS), SRP14 (Affinity Capture-MS), SRSF8 (Affinity Capture-MS), RAB11FIP2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), GPKOW (Affinity Capture-MS), ZCCHC10 (Affinity Capture-MS), CCDC94 (Affinity Capture-MS), MUC13 (Affinity Capture-MS), SNIP1 (Affinity Capture-MS), ZNF668 (Affinity Capture-MS), FAM192A (Affinity Capture-MS), TOE1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B7P9G0, A0A0R4IMY7, A0JPA0, D3ZAA9, O35454, P0C1Q3, P0C588, P16067, P20594, P32232, P33402, P35525, P46197, P47823, P51432, P51788, Q01970, Q13144, Q14168, Q1LWG4, Q32PX9, Q3TWN3, Q3USB7, Q3V384, Q4U2V3, Q502J0, Q5EBA1, Q5U2P1, Q62688, Q66K14, Q69ZF7, Q6P4Q7, Q7L5N7, Q80YD1, Q8BYI6, Q8CIR4, Q8IYB8, Q8K394, Q8WV93, Q91WT9

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, P21564, P35522, P35523, P35524, P51800, P51801, P51802, P51803

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	19
Uncertain significance	368
Likely benign	192
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100630	NM_004366.6(CLCN2):c.430_435del (p.Leu144_Ile145del)	Pathogenic
100631	NM_004366.6(CLCN2):c.1499C>T (p.Ala500Val)	Pathogenic
100632	NM_004366.6(CLCN2):c.828dup (p.Arg277fs)	Pathogenic
1032901	NM_004366.6(CLCN2):c.985_986del (p.Ile329fs)	Pathogenic
217787	NM_004366.6(CLCN2):c.1113delinsACTGCTCAT (p.Ser375fs)	Pathogenic
217788	NM_004366.6(CLCN2):c.1143del (p.Gly382fs)	Pathogenic
2418913	NM_004366.6(CLCN2):c.2257C>T (p.Arg753Ter)	Pathogenic
2573522	NM_004366.6(CLCN2):c.211C>T (p.Arg71Ter)	Pathogenic
2627936	NM_004366.6(CLCN2):c.1382_1386del (p.Pro461fs)	Pathogenic
2699999	NM_004366.6(CLCN2):c.1912dup (p.Ala638fs)	Pathogenic
2834626	NM_004366.6(CLCN2):c.1424_1427dup (p.Ser476fs)	Pathogenic
3068719	NM_004366.6(CLCN2):c.61dup (p.Leu21fs)	Pathogenic
3391843	GRCh37/hg19 3q26.31-29(chr3:174764228-197851986)x3	Pathogenic
3652717	NM_004366.6(CLCN2):c.2408T>A (p.Leu803Ter)	Pathogenic
3718367	NM_004366.6(CLCN2):c.1116_1123dup (p.Ser375fs)	Pathogenic
441164	NM_004366.6(CLCN2):c.515G>A (p.Arg172Gln)	Pathogenic
441165	NM_004366.6(CLCN2):c.65T>A (p.Met22Lys)	Pathogenic
441166	NM_004366.6(CLCN2):c.76T>A (p.Tyr26Asn)	Pathogenic
441167	NM_004366.6(CLCN2):c.1084A>T (p.Lys362Ter)	Pathogenic
441168	NM_004366.6(CLCN2):c.2593A>C (p.Ser865Arg)	Pathogenic
4765171	NM_004366.6(CLCN2):c.1541_1542del (p.Thr514fs)	Pathogenic
813301	NM_004366.6(CLCN2):c.1397-1G>A	Pathogenic
863631	NM_004366.6(CLCN2):c.2136_2137del (p.Pro713fs)	Pathogenic
980554	GRCh37/hg19 3q27.1-27.3(chr3:182877291-186830759)x1	Pathogenic
1194517	NM_004366.6(CLCN2):c.898+1G>A	Likely pathogenic
1300131	NM_004366.6(CLCN2):c.1550C>T (p.Thr517Met)	Likely pathogenic
217785	NM_004366.6(CLCN2):c.925C>T (p.Arg309Ter)	Likely pathogenic
217791	NM_004366.6(CLCN2):c.1412G>A (p.Arg471His)	Likely pathogenic
217796	NM_004366.6(CLCN2):c.2386C>T (p.Gln796Ter)	Likely pathogenic
2439141	NM_004366.6(CLCN2):c.207C>A (p.Cys69Ter)	Likely pathogenic

SpliceAI

4323 predictions. Top by Δscore:

Variant	Effect	Δscore
3:184352007:CCCTA:C	donor_loss	1.0000
3:184352008:CCTAC:C	donor_loss	1.0000
3:184352009:CTA:C	donor_loss	1.0000
3:184352010:TACC:T	donor_loss	1.0000
3:184352011:ACCT:A	donor_loss	1.0000
3:184352115:AATC:A	acceptor_loss	1.0000
3:184352116:AT:A	acceptor_gain	1.0000
3:184352117:TC:T	acceptor_loss	1.0000
3:184352118:C:CC	acceptor_gain	1.0000
3:184352118:CTGA:C	acceptor_loss	1.0000
3:184352328:CACT:C	acceptor_gain	1.0000
3:184352330:CT:C	acceptor_gain	1.0000
3:184352332:C:CC	acceptor_gain	1.0000
3:184352437:A:AC	donor_gain	1.0000
3:184352438:C:CC	donor_gain	1.0000
3:184352441:A:AC	donor_gain	1.0000
3:184352441:ACTG:A	donor_gain	1.0000
3:184352442:C:CT	donor_gain	1.0000
3:184352442:CTG:C	donor_gain	1.0000
3:184352442:CTGC:C	donor_gain	1.0000
3:184352505:T:C	acceptor_gain	1.0000
3:184352505:T:TC	acceptor_gain	1.0000
3:184352508:T:C	acceptor_gain	1.0000
3:184352508:T:TC	acceptor_gain	1.0000
3:184352515:C:CT	acceptor_gain	1.0000
3:184352515:C:T	acceptor_gain	1.0000
3:184352516:A:T	acceptor_gain	1.0000
3:184352520:C:T	acceptor_gain	1.0000
3:184352535:T:TC	acceptor_gain	1.0000
3:184352541:T:TC	acceptor_gain	1.0000

AlphaMissense

5805 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:184346799:A:G	L835P	1.000
3:184346948:A:T	V830D	1.000
3:184346954:C:A	G828V	1.000
3:184346954:C:T	G828E	1.000
3:184346955:C:G	G828R	1.000
3:184346955:C:T	G828R	1.000
3:184346960:A:G	L826P	1.000
3:184346966:C:A	G824V	1.000
3:184346966:C:T	G824D	1.000
3:184346978:A:T	V820D	1.000
3:184352038:A:G	L797P	1.000
3:184353404:C:T	G625D	1.000
3:184353405:C:G	G625R	1.000
3:184354137:A:G	L562P	1.000
3:184354251:A:G	L524P	1.000
3:184354255:C:T	E523K	1.000
3:184354556:G:T	A500D	1.000
3:184354634:C:T	G474D	1.000
3:184354635:C:G	G474R	1.000
3:184354646:C:T	G470E	1.000
3:184354939:A:T	V454D	1.000
3:184357074:C:T	G335E	1.000
3:184357075:C:G	G335R	1.000
3:184357075:C:T	G335R	1.000
3:184357083:C:T	G332D	1.000
3:184357084:C:G	G332R	1.000
3:184357182:C:T	G328D	1.000
3:184357183:C:G	G328R	1.000
3:184357191:G:T	A325D	1.000
3:184357193:A:C	F324L	1.000

dbSNP variants (sampled 300 via entrez): RS1000196001 (3:184361647 G>A,C), RS1000268648 (3:184356675 C>T), RS1000284149 (3:184356510 A>G), RS1000490246 (3:184351673 T>G), RS1000598155 (3:184355622 C>T), RS1000674813 (3:184347180 GTAATAA>G,GTAA), RS1000704403 (3:184346918 G>A), RS1000967823 (3:184352436 T>C,G), RS1001141188 (3:184361539 C>G,T), RS1001314561 (3:184358338 C>A,T), RS1001372353 (3:184352651 G>A), RS1001581853 (3:184358377 G>A), RS1001733658 (3:184352795 G>A), RS1002063100 (3:184362649 G>C), RS1002095768 (3:184363089 A>G)

Disease associations

OMIM: gene MIM:600570 | disease phenotypes: MIM:605635, MIM:607628, MIM:615651, MIM:617116

GenCC curated gene-disease

Disease	Classification	Inheritance
leukoencephalopathy with mild cerebellar ataxia and white matter edema	Definitive	Autosomal recessive
epilepsy, idiopathic generalized, susceptibility to, 11	Strong	Autosomal dominant
familial hyperaldosteronism type II	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
epilepsy	Refuted	AD

Mondo (10): familial hyperaldosteronism type II (MONDO:0011576), epilepsy, idiopathic generalized, susceptibility to, 11 (MONDO:0011875), leukoencephalopathy with mild cerebellar ataxia and white matter edema (MONDO:0014292), epilepsy (MONDO:0005027), hereditary ataxia (MONDO:0100309), intellectual disability (MONDO:0001071), epilepsy, familial focal, with variable foci 2 (MONDO:0014924), cerebellar ataxia (MONDO:0000437), bipolar disorder (MONDO:0004985), cerebral palsy (MONDO:0006497)

Orphanet (6): Juvenile myoclonic epilepsy (Orphanet:307), Leukoencephalopathy with mild cerebellar ataxia and white matter edema (Orphanet:363540), Familial hyperaldosteronism type II (Orphanet:404), Hereditary ataxia (Orphanet:183518), Rare ataxia (Orphanet:102002), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000153	Abnormality of the mouth
HP:0000360	Tinnitus
HP:0000421	Epistaxis
HP:0000496	Abnormality of eye movement
HP:0000533	Chorioretinal atrophy
HP:0000718	Aggressive behavior
HP:0000822	Hypertension
HP:0000859	Increased circulating aldosterone concentration
HP:0001123	Visual field defect
HP:0001138	Optic neuropathy
HP:0001249	Intellectual disability
HP:0001324	Muscle weakness
HP:0002018	Nausea
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002133	Status epilepticus
HP:0002170	Intracranial hemorrhage
HP:0002197	Generalized-onset seizure
HP:0002315	Headache
HP:0002345	Action tremor
HP:0002352	Leukoencephalopathy
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002392	EEG with polyspike wave complexes
HP:0002900	Hypokalemia
HP:0003596	Middle age onset
HP:0003621	Juvenile onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006269_778	General cognitive ability	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D001714	Bipolar Disorder	F03.600.150.500
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002547	Cerebral Palsy	C10.228.140.140.254
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C531684	Hereditary spinal ataxia (supp.)
C565312	Hyperaldosteronism, Familial, Type II (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1628478 (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
GaTx2	Channel blocker	10.8	pKd

ChEMBL bioactivities

17 potent at pChembl≥5 of 35 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL6028327
6.70	IC50	200	nM	CHEMBL5788508
6.52	IC50	300	nM	CHEMBL541236
6.21	IC50	620	nM	CHEMBL6028327
6.16	IC50	700	nM	CHEMBL5889110
5.94	IC50	1160	nM	CHEMBL5805089
5.92	IC50	1200	nM	CHEMBL5948077
5.75	IC50	1790	nM	CHEMBL5889110
5.69	IC50	2040	nM	CHEMBL5989739
5.53	IC50	2980	nM	CHEMBL6028327
5.44	IC50	3600	nM	CHEMBL5836670
5.28	IC50	5290	nM	CHEMBL5960497
5.14	IC50	7160	nM	CHEMBL5847123
5.13	IC50	7320	nM	CHEMBL5943764
5.11	IC50	7690	nM	CHEMBL5813798
5.10	IC50	7930	nM	CHEMBL5882967
5.01	IC50	9860	nM	CHEMBL5783762

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases response to substance	2
GSK-J4	decreases expression	1
potassium perchlorate	decreases expression	1
trichostatin A	decreases expression	1
butyraldehyde	decreases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
Lubiprostone	affects transport, increases reaction, increases activity	1
Sunitinib	decreases expression	1
Chlorides	affects transport, increases reaction	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5737523	Binding	Binding Assay: CLC-2 activity using cell-free assays, e.g., binding assays; with purified enzymes.	Compositions and methods to modulate chloride ion channel activity

Cellosaurus cell lines

5 cell lines: 2 transformed cell line, 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_E7X1	HEK-293 hClc-2	Transformed cell line	Female
CVCL_E9Y1	HEK293-CLCN2-RFP	Transformed cell line	Female
CVCL_SJ15	HAP1 CLCN2 (-) 1	Cancer cell line	Male
CVCL_SJ16	HAP1 CLCN2 (-) 2	Cancer cell line	Male
CVCL_YT42	SKLOi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy