CLIC1

Summary

CLIC1 (CLIC family member 1, HGNC:2062) is a protein-coding gene on chromosome 6p21.33, encoding Chloride intracellular channel protein 1 (O00299). In the soluble state, catalyzes glutaredoxin-like thiol disulfide exchange reactions with reduced glutathione as electron donor.

Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 1 is a member of the p64 family; the protein localizes principally to the cell nucleus and exhibits both nuclear and plasma membrane chloride ion channel activity.

Source: NCBI Gene 1192 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 34 total
• Druggable target: yes
• MANE Select transcript: NM_001288

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2062
Approved symbol	CLIC1
Name	CLIC family member 1
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	NCC27, p64CLCP, G6, CLCNL1
Ensembl gene	ENSG00000213719
Ensembl biotype	protein_coding
OMIM	602872
Entrez	1192

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000375779, ENST00000375780, ENST00000375784, ENST00000395892, ENST00000616760, ENST00000864995, ENST00000864996, ENST00000864997, ENST00000864998, ENST00000918465, ENST00000918466, ENST00000918467, ENST00000947457, ENST00000947458, ENST00000947459

RefSeq mRNA: 3 — MANE Select: NM_001288 NM_001287593, NM_001287594, NM_001288

CCDS: CCDS4719

Canonical transcript exons

ENST00000375784 — 6 exons

Exon	Start	End
ENSE00001628385	31732217	31732398
ENSE00001649936	31733566	31733672
ENSE00001732257	31733836	31733961
ENSE00001754230	31734154	31734263
ENSE00001858405	31736262	31736530
ENSE00003967607	31730599	31731003

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 291.2135 / max 1275.6449, expressed in 1827 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72811	150.7927	1823
72808	127.0971	1826
72810	10.3979	1596
72809	2.8775	1421
72812	0.0483	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.52	gold quality
blood	UBERON:0000178	99.46	gold quality
leukocyte	CL:0000738	99.43	gold quality
monocyte	CL:0000576	99.42	gold quality
mucosa of transverse colon	UBERON:0004991	99.39	gold quality
lower esophagus mucosa	UBERON:0035834	99.35	gold quality
rectum	UBERON:0001052	99.34	gold quality
gall bladder	UBERON:0002110	99.33	gold quality
islet of Langerhans	UBERON:0000006	99.28	gold quality
placenta	UBERON:0001987	99.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.28	gold quality
right lung	UBERON:0002167	99.24	gold quality
vermiform appendix	UBERON:0001154	99.23	gold quality
upper lobe of left lung	UBERON:0008952	99.20	gold quality
lymph node	UBERON:0000029	99.19	gold quality
spleen	UBERON:0002106	99.19	gold quality
esophagus mucosa	UBERON:0002469	99.19	gold quality
descending thoracic aorta	UBERON:0002345	99.17	gold quality
smooth muscle tissue	UBERON:0001135	99.16	gold quality
skin of abdomen	UBERON:0001416	99.16	gold quality
zone of skin	UBERON:0000014	99.12	gold quality
transverse colon	UBERON:0001157	99.11	gold quality
right coronary artery	UBERON:0001625	99.11	gold quality
skin of leg	UBERON:0001511	99.10	gold quality
thoracic aorta	UBERON:0001515	99.10	gold quality
ascending aorta	UBERON:0001496	99.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.08	gold quality
lung	UBERON:0002048	99.05	gold quality
adipose tissue	UBERON:0001013	99.04	gold quality
left coronary artery	UBERON:0001626	99.02	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	80.77
E-CURD-122	yes	39.35
E-GEOD-135922	yes	38.99
E-MTAB-10287	yes	31.99
E-CURD-88	yes	28.47
E-MTAB-9067	yes	20.52
E-HCAD-9	yes	16.16
E-HCAD-5	yes	14.25
E-MTAB-9388	yes	13.95
E-MTAB-10042	yes	13.46
E-CURD-10	no	497.08
E-HCAD-6	no	20.01
E-MTAB-8410	no	10.26
E-MTAB-9801	no	5.58
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting CLIC1, 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-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-4724-5P	98.87	67.75	1324
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-4669	97.94	62.71	224
HSA-MIR-122-5P	97.23	64.92	1024
HSA-MIR-7847-3P	96.63	64.58	952
HSA-MIR-3657	96.33	66.29	608
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-1229-5P	94.57	65.78	487

Literature-anchored findings (GeneRIF, showing 40)

• By selectively tagging either N- or C-termini of NCC27 (CLIC1) and varying the side of the membrane from which channel activity is recorded, NCC27 can be seen to be a TM protein forming part of an ion channel. (PMID:10834939)
• NCC27 (CLIC1) is broadly expressed and highly conserved. NCC27 blockers led to arrest of CHO-K1 cells in the G2/M stage of the cell cycle, the same stage at which this ion channel is selectively expressed on the plasma membrane (PMID:11195932)
• The soluble form of CLIC1 has been determined at 1.4-A resolution. The protein is monomeric and structurally homologous to the glutathione S-transferase superfamily, and it has a redox-active site resembling glutaredoxin. (PMID:11551966)
• Soluble E. coli-derived recombinant CLIC1 moves from solution into artificial bilayers and forms chloride-selective ion channels with essentially identical properties to those observed in CLIC1-transfected CHO cells. (PMID:11978800)
• The structure of oxidized CLIC1 has been determined. The oxidized CLIC1 dimer maintains its ability to form chloride ion channels in artificial bilayers and vesicles, whereas a reducing environment prevents the formation of ion channels by CLIC1 (PMID:14613939)
• on oxidation CLIC1 undergoes a reversible transition from a monomeric to a non-covalent dimeric state due to the formation of an intramolecular disulfide bond (Cys-24-Cys-59) (PMID:14613939)
• Amyloid-b stimulation of neonatal rat microglia increases CLIC1 protein and functional expression of CLIC1 chloride conductance. Blocking CLIC1 or reducing it by siRNA in amyloid-b treated microglia cocultured with neurons inhibits neurotoxicity (PMID:15190104)
• insulin induces the proteasome-dependent degradation of SRp20 as well as the subnuclear relocalization of CLIC1 (PMID:15827065)
• In certain polarized columnar epithelia, CLIC1 may play a role in apical membrane recycling. (PMID:17326840)
• CFTR confers cAMP regulation to CLIC1 activity in the plasma membrane (PMID:17347778)
• Data showed that CLIC1 and CLIC5, but not CLIC4, were strongly and reversibly inhibited (or inactivated) by F-actin. (PMID:18028448)
• CLIC1 and TPD52 were significantly (P<0.05) up-regulated in all cases of colorectal cancer investigated, irrespective of localization, pTNM stage and grade of colon cancer. (PMID:18710659)
• Acid-induced destabilization and partial unfolding of CLIC1 involve helix alpha1 which is the major structural element of the transmembrane region. (PMID:18850721)
• Overexpression of CLIC1 promoted cell motility & invasion of gallbladder carcinoma cell lines in vitro, while RNA interference of CLIC1 remarkably decreased these. CLIC1 might play an important role in metastasis of gallbladder carcinoma. (PMID:19299076)
• CLIC1 may play a role in the regulation of osteoblastic differentiation from mesenchymal progenitors, although its physiologic role in osteoblasts remains to be determined. (PMID:19703605)
• statistical analysis of CLIC1 level in plasma shows that CLIC1 could be applied as a marker for early detection of nasopharyngeal carcinoma (PMID:19845400)
• Suppression of CLIC1 contributes to acquisition of the radioresistance phenotype of laryngeal cancer cells via inhibition of reactive oxygen species production. (PMID:20461716)
• Consistent with previous findings, the N-terminal domain of CLIC1 is likely to insert into the lipid bilayer, while the C-domain remains in solution on the extravesicular side of the membrane (PMID:20507120)
• Data show that the expression of HSP27 and CLIC1 was strongly positive in 61 (59.2%) and 49 cases (47.6%), respectively. (PMID:21858536)
• Intermolecular FRET data suggest that (1) N-terminal domain of CLIC1 inserts into bilayer as extended alpha-helix, (2) CLIC1 forms oligomer upon oxidation in presence of membranes, and (3) CLIC1 inserts into bilayer as oligomer of 6-8 subunits. (PMID:22082111)
• knockdown of PA28beta could enhance tumor invasion and metastasis, at least in part, through up-regulation of CLIC1 in gastric adenocarcinoma (PMID:22173998)
• Both histidine (His)74 and His185 are involved in triggering pH changes to the conformational stability of wild-type CLIC1 via their protonation, which stabilizes the intermediate state. (PMID:22242893)
• CLIC1 regulates the migration and invasion of colon cancer cells. (PMID:22426742)
• the first evidence that CLIC1 expression might play an important role in the regulation of aggressiveness in human gliomas (PMID:22578365)
• High CLIC1 expression can efficiently inhibit proliferation and enhance apoptosis, migration and invasion of gastric cancer cells in vitro. (PMID:22791942)
• cholesterol dependent behaviour of CLIC1 (PMID:23457643)
• increased CLIC1 protein expression is associated with clinicopathological factors and a poor prognosis of hepatic tumors. (PMID:23593969)
• In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. (PMID:23792823)
• Mutation of the two charged amino acids (K37 and R29) in the putative transmembrane region of CLIC1 alters the biophysical properties of the ion channel in both artificial bilayers and cells. (PMID:24058583)
• our results are consistent with a model of CLIC function in which covalent binding of glutathione does not occur spontaneously but requires interaction with another protein to stabilise the GSH binding site and/or transfer of the ligand (PMID:24089665)
• Reduced gliomagenesis after CLIC1 targeting in tumoral stem/progenitor cells and the finding that CLIC1 expression is inversely associated with patient survival suggest CLIC1 as a potential target and prognostic biomarker. (PMID:24115360)
• We have identified a cation-pi interaction involving Lys37. Although this residue is not required for folding, membrane binding, or insertion, it does facilitate CLIC1 transmembrane domain self-association. (PMID:24328417)
• CLIC1 protein is involved in the metastasis of colon cancer LOVO cells via regulating the ROS/ERK pathway in the hypoxia-reoxygenation process (PMID:24587680)
• Data indicate the chloride channel protein CLIC1 as the most penetrant receptor. (PMID:24661138)
• It participates in migration and invasion of hepatocellular carcinoma by targeting maspin. (PMID:24989236)
• Results indicate that CLIC1 is an important contributor to tumor invasion, metastasis, and angiogenesis. (PMID:25205595)
• Data show that glutamate 85 and glutamate 228 are pH-sensor residues of chloride intracellular channel protein CLIC1 and contribute to the pH-response stability in different ways. (PMID:25209805)
• The expression of CLIC1 is closely related to the progression of gall bladder cancer and may be used as an effective marker for predicting the prognosis of this disease. (PMID:25227665)
• Results indicate that CLIC1 could regulate prostate cancer cell proliferation and migration by regulating the(MAPK)/ERK pathway. (PMID:25279971)
• CLIC1 and CLIC4 are overexpressed in specific tumor types or their corresponding stroma and change localization and function from hydrophilic cytosolic to integral transmembrane proteins. (Review) (PMID:25546839)

Cross-species orthologs

34 orthologs

Organism	Symbol	Gene ID
danio_rerio	clic1	ENSDARG00000103340
mus_musculus	Clic1	ENSMUSG00000007041
rattus_norvegicus	Clic1	ENSRNOG00000029682
drosophila_melanogaster	GstD1	FBGN0001149
drosophila_melanogaster	GstD2	FBGN0010038
drosophila_melanogaster	GstD3	FBGN0010039
drosophila_melanogaster	GstD4	FBGN0010040
drosophila_melanogaster	GstD5	FBGN0010041
drosophila_melanogaster	GstD6	FBGN0010042
drosophila_melanogaster	GstD7	FBGN0010043
drosophila_melanogaster	GstD8	FBGN0010044
drosophila_melanogaster	GstE12	FBGN0027590
drosophila_melanogaster	Clic	FBGN0030529
drosophila_melanogaster	GstT3	FBGN0031117
drosophila_melanogaster	GstE13	FBGN0033381
drosophila_melanogaster	GstE1	FBGN0034335
drosophila_melanogaster	GstE11	FBGN0034354
drosophila_melanogaster	GstD9	FBGN0038020
drosophila_melanogaster	GstD10	FBGN0042206
drosophila_melanogaster	GstT1	FBGN0050000
drosophila_melanogaster	GstT2	FBGN0050005
drosophila_melanogaster	GstE9	FBGN0063491
drosophila_melanogaster	GstE8	FBGN0063492
drosophila_melanogaster	GstE7	FBGN0063493
drosophila_melanogaster	GstE6	FBGN0063494
drosophila_melanogaster	GstE5	FBGN0063495
drosophila_melanogaster	GstE4	FBGN0063496
drosophila_melanogaster	GstE3	FBGN0063497
drosophila_melanogaster	GstE2	FBGN0063498
drosophila_melanogaster	GstE10	FBGN0063499
caenorhabditis_elegans	exc-4	WBGENE00001365
caenorhabditis_elegans		WBGENE00001371
caenorhabditis_elegans	gst-43	WBGENE00001791
caenorhabditis_elegans		WBGENE00021817

Paralogs (14): GSTO2 (ENSG00000065621), GSTT2 (ENSG00000099984), GSTZ1 (ENSG00000100577), GDAP1 (ENSG00000104381), CLIC5 (ENSG00000112782), GDAP1L1 (ENSG00000124194), GSTT2B (ENSG00000133433), GSTO1 (ENSG00000148834), CLIC2 (ENSG00000155962), CLIC6 (ENSG00000159212), CLIC4 (ENSG00000169504), CLIC3 (ENSG00000169583), EEF1G (ENSG00000254772), GSTT4 (ENSG00000276950)

Protein

Protein identifiers

Chloride intracellular channel protein 1 — O00299 (reviewed: O00299)

Alternative names: Chloride channel ABP, Glutaredoxin-like oxidoreductase CLIC1, Glutathione-dependent dehydroascorbate reductase CLIC1, Nuclear chloride ion channel 27, Regulatory nuclear chloride ion channel protein

All UniProt accessions (2): O00299, Q5SRT3

UniProt curated annotations — full annotation on UniProt →

Function. In the soluble state, catalyzes glutaredoxin-like thiol disulfide exchange reactions with reduced glutathione as electron donor. Reduces selenite and dehydroascorbate and may act as an antioxidant during oxidative stress response. Can insert into membranes and form voltage-dependent multi-ion conductive channels. Membrane insertion seems to be redox-regulated and may occur only under oxidizing conditions. Involved in regulation of the cell cycle.

Subunit / interactions. Monomer. Homodimer (in vitro). Interacts with TRAPPC2. Dimerization requires a conformation change that leads to the exposure of a large hydrophobic surface. In vivo, this may lead to membrane insertion. Interacts with AKAP9.

Subcellular location. Nucleus. Nucleus membrane. Cytoplasm. Cell membrane. Endoplasmic reticulum.

Tissue specificity. Expression is prominent in heart, placenta, liver, kidney and pancreas.

Post-translational modifications. Hydrogen peroxide treatment causes a conformation change, leading to dimerization and formation of an intramolecular disulfide bond between Cys-24 and Cys-59.

Activity regulation. The oxidoreductase activity is inhibited by rapamycin, amphotericin B and IAA-94. The channel conductance is regulated by pH and redox membrane potential. Inhibited by IAA-94.

Domain organisation. The active G-site contains a monothiol Cys-X-X-Ser motif which mediates glutathione-dependent redox catalysis. Members of this family may change from a globular, soluble state to a state where the N-terminal domain is inserted into the membrane and functions as a channel. The redox status of the active cysteine in Cys-X-X-Cys/Ser motif likely determines the capacity to adopt a soluble or membrane-inserted state. A conformation change of the N-terminal domain is thought to expose hydrophobic surfaces that trigger membrane insertion.

Miscellaneous. The protein seems to have very low affinity for glutathione, even though glutathione binding was observed in protein crystals.

Similarity. Belongs to the chloride channel CLIC family.

RefSeq proteins (3): NP_001274522, NP_001274523, NP_001279* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002946	CLIC	Family
IPR010987	Glutathione-S-Trfase_C-like	Domain
IPR030259	CLIC-1_C	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR036282	Glutathione-S-Trfase_C_sf	Homologous_superfamily
IPR040079	Glutathione_S-Trfase	Family
IPR053823	CLIC_N	Domain

Pfam: PF13410, PF22441

Catalyzed reactions (Rhea), 7 shown:

• L-dehydroascorbate + 2 glutathione = glutathione disulfide + L-ascorbate (RHEA:24424)
• 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)
• fluoride(in) = fluoride(out) (RHEA:76159)

UniProt features (48 total): helix 14, modified residue 9, strand 7, mutagenesis site 5, binding site 3, turn 2, initiator methionine 1, chain 1, disulfide bond 1, transmembrane region 1, sequence conflict 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
4K0N	X-RAY DIFFRACTION	1.25
4JZQ	X-RAY DIFFRACTION	1.35
1K0M	X-RAY DIFFRACTION	1.4
4K0G	X-RAY DIFFRACTION	1.4
3O3T	X-RAY DIFFRACTION	1.7
1K0O	X-RAY DIFFRACTION	1.75
3QR6	X-RAY DIFFRACTION	1.78
1RK4	X-RAY DIFFRACTION	1.79
1K0N	X-RAY DIFFRACTION	1.8
7FBQ	X-RAY DIFFRACTION	1.8
3UVH	X-RAY DIFFRACTION	1.84
3P8W	X-RAY DIFFRACTION	2
3P90	X-RAY DIFFRACTION	2.3
3TGZ	X-RAY DIFFRACTION	2.3
3SWL	X-RAY DIFFRACTION	2.35
4IQA	X-RAY DIFFRACTION	2.49
7F8R	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00299-F1	94.34	0.90

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 (3): 24; 64; 77

Post-translational modifications (9): 13, 24, 119, 121, 131, 156, 211, 233, 2

Disulfide bonds (1): 24–59

Mutagenesis-validated functional residues (5):

Position	Phenotype
24	loss of glutathione-dependent oxidoreductase activity. reduces channel conductance and abolishes its dependence on membr
24	loss of dimerization and of ion transport activity.
37	decreases glutathione-dependent oxidoreductase activity.
59	loss of glutathione-dependent oxidoreductase activity.
59	loss of dimerization and of ion transport activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 342 (showing top): AP1_01, GNF2_MSN, GNF2_BNIP2, MODULE_151, GOBP_PLATELET_ACTIVATION, GCM_NPM1, MORF_UBE2I, HSIAO_HOUSEKEEPING_GENES, GOBP_OSTEOBLAST_DIFFERENTIATION, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_INORGANIC_ANION_TRANSPORT, TGACCTY_ERR1_Q2, MODULE_352, GOBP_WOUND_HEALING, GOBP_CELL_CELL_ADHESION

GO Biological Process (8): chloride transport (GO:0006821), signal transduction (GO:0007165), positive regulation of osteoblast differentiation (GO:0045669), regulation of mitochondrial membrane potential (GO:0051881), platelet aggregation (GO:0070527), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), chloride transmembrane transport (GO:1902476)

GO Molecular Function (5): chloride channel activity (GO:0005254), glutathione dehydrogenase (ascorbate) activity (GO:0045174), cadherin binding (GO:0045296), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (16): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nuclear envelope (GO:0005635), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), brush border (GO:0005903), membrane (GO:0016020), nuclear membrane (GO:0031965), vesicle (GO:0031982), chloride channel complex (GO:0034707), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), monoatomic ion channel complex (GO:0034702)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membrane-bounded organelle	3
cytoplasm	3
nucleus	2
endomembrane system	2
monoatomic anion transport	1
inorganic anion transport	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
regulation of membrane potential	1
platelet activation	1
homotypic cell-cell adhesion	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
glutathione disulfide oxidoreductase activity	1
antioxidant activity	1
oxidoreductase activity, acting on a sulfur group of donors, quinone or similar compound as acceptor	1
cell adhesion molecule binding	1
binding	1
catalytic activity	1
organelle envelope	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
microvillus	1
apical part of cell	1
cluster of actin-based cell projections	1
nuclear envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1658 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLIC1	MAPK15	Q8TD08	838
CLIC1	PHC3	Q8NDX5	717
CLIC1	CLCN4	P51793	672
CLIC1	ANXA2	P07355	567
CLIC1	AKT1	P31749	539
CLIC1	EZR	P15311	526
CLIC1	CLCN3	P51790	493
CLIC1	S100A11	P31949	493
CLIC1	ALDOA	P04075	471
CLIC1	ANXA5	P08758	469
CLIC1	J3KPS3	J3KPS3	465
CLIC1	CAV1	Q03135	459
CLIC1	SH2D3C	Q8N5H7	457
CLIC1	GSTO1	P78417	447
CLIC1	ATP1A2	P50993	438

IntAct

132 interactions, top by confidence:

A	B	Type	Score
CFTR	CLIC1	psi-mi:“MI:0915”(physical association)	0.790
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CLIC1	TPRN	psi-mi:“MI:0914”(association)	0.670
CLIC1	LSM1	psi-mi:“MI:0915”(physical association)	0.670
CLIC1	TPRN	psi-mi:“MI:0915”(physical association)	0.670
PSMD10	CLIC1	psi-mi:“MI:0914”(association)	0.650
PSMD10	CLIC1	psi-mi:“MI:0407”(direct interaction)	0.650
PSMD10	CLIC1	psi-mi:“MI:0915”(physical association)	0.650
CLIC1	PSMD10	psi-mi:“MI:0915”(physical association)	0.650
NHSL2	CLIC1	psi-mi:“MI:0915”(physical association)	0.560
CLIC1	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
CLIC1	NHSL2	psi-mi:“MI:0915”(physical association)	0.560
SDF2L1	CLIC1	psi-mi:“MI:0914”(association)	0.530
STAT3	CLIC1	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (200): CLIC1 (Affinity Capture-Western), CLIC1 (Reconstituted Complex), CLIC1 (Affinity Capture-MS), LSM1 (Two-hybrid), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), CLIC1 (Co-fractionation), DDB1 (Co-fractionation)

ESM2 similar proteins: A0A1L5BUX8, A0A1U8QXK4, A0A1U9YI21, B5BP46, C8VQ63, D4Z909, M1W426, O00299, O04487, O15247, O45405, O74830, P12261, P21161, P26642, P30111, P34345, P36008, P40921, P42936, P43387, Q00717, Q4WB03, Q5E9B7, Q5M883, Q5R957, Q5Z627, Q6MG61, Q6NMS0, Q6YW46, Q8BXK9, Q8WQA4, Q91375, Q95MF9, Q9CA57, Q9CAS6, Q9EPT8, Q9FUM1, Q9FUS6, Q9FUT0

Diamond homologs: O00299, O15247, O95833, P35526, Q29238, Q5E9B7, Q5M883, Q5R957, Q6MG61, Q811Q2, Q8BHB9, Q8BXK9, Q95MF9, Q96NY7, Q9D7P7, Q9EPT8, Q9N2G5, Q9NZA1, Q9QYB1, Q9XSA7, Q9Y696, Q9Z0W7, Q9Z1Q5, O45405, Q9VY78, P81124, Q9FRL8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1016 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31730999:ACCAC:A	acceptor_gain	1.0000
6:31731000:CCAC:C	acceptor_gain	1.0000
6:31731000:CCACC:C	acceptor_gain	1.0000
6:31731001:CAC:C	acceptor_gain	1.0000
6:31731001:CACC:C	acceptor_gain	1.0000
6:31731002:AC:A	acceptor_gain	1.0000
6:31731003:CC:C	acceptor_gain	1.0000
6:31731004:C:CA	acceptor_loss	1.0000
6:31731004:C:CC	acceptor_gain	1.0000
6:31731004:C:T	acceptor_gain	1.0000
6:31731010:A:AC	acceptor_gain	1.0000
6:31731010:A:C	acceptor_gain	1.0000
6:31732285:T:TA	donor_gain	1.0000
6:31732394:CAGAT:C	acceptor_gain	1.0000
6:31732396:GAT:G	acceptor_gain	1.0000
6:31732399:C:CC	acceptor_gain	1.0000
6:31732399:C:CG	acceptor_loss	1.0000
6:31732401:G:C	acceptor_gain	1.0000
6:31732401:G:GC	acceptor_gain	1.0000
6:31733556:CAAGA:C	donor_gain	1.0000
6:31733562:TCAC:T	donor_loss	1.0000
6:31733564:A:AC	donor_gain	1.0000
6:31733564:ACTGT:A	donor_gain	1.0000
6:31733565:C:CA	donor_gain	1.0000
6:31733565:CT:C	donor_gain	1.0000
6:31733565:CTG:C	donor_gain	1.0000
6:31733565:CTGT:C	donor_gain	1.0000
6:31733565:CTGTC:C	donor_gain	1.0000
6:31733668:GGTAC:G	acceptor_gain	1.0000
6:31733669:GTAC:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000211682 (6:31732963 A>C,T), RS1000238815 (6:31730980 T>C), RS1000242585 (6:31732712 A>G), RS1000265313 (6:31731565 G>C), RS1000398315 (6:31738730 CT>C), RS1000678330 (6:31737077 TC>T), RS1000871989 (6:31739268 C>CT), RS1001561816 (6:31738107 C>A), RS1001633527 (6:31738468 G>A), RS1001808204 (6:31730391 T>C), RS1001886375 (6:31734997 C>G,T), RS1001919300 (6:31734781 A>G), RS1002628722 (6:31737606 G>T), RS1003006476 (6:31738055 G>C), RS1003032668 (6:31730243 C>G)

Disease associations

OMIM: gene MIM:602872 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_224	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_281	Autism spectrum disorder or schizophrenia	5.000000e-09
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST004599_225	Mean platelet volume	3.000000e-36
GCST008916_111	Asthma	2.000000e-14
GCST008916_30	Asthma	1.000000e-09
GCST008917_2	Asthma (childhood onset)	4.000000e-07
GCST008921_1	Asthma and major depressive disorder	2.000000e-16
GCST010988_357	Adult body size	4.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067062 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.05	IC50	9000	nM	CHEMBL541236

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases expression	4
Aflatoxin B1	increases expression, affects expression, decreases methylation	3
Benzo(a)pyrene	increases expression, increases methylation	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	increases metabolic processing, affects expression	2
Cyclosporine	increases expression	2
beta-Naphthoflavone	increases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
salinomycin	decreases expression	1
terbufos	decreases methylation	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
ferrous chloride	increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	increases phosphorylation	1
artenimol	affects binding	1
CGP 52608	affects binding, increases reaction	1
CD 437	decreases expression	1
chloropicrin	affects 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, increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
ON 01910	increases expression	1
10-(octyloxy)decyl-2-(trimethylammonium)ethyl phosphate	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651122	Binding	Binding affinity to human CLIC1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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