CLIC4

Summary

CLIC4 (CLIC family member 4, HGNC:13518) is a protein-coding gene on chromosome 1p36.11, encoding Chloride intracellular channel protein 4 (Q9Y696). 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 4 (CLIC4) protein, encoded by the CLIC4 gene, is a member of the p64 family; the gene is expressed in many tissues and exhibits a intracellular vesicular pattern in Panc-1 cells (pancreatic cancer cells).

Source: NCBI Gene 25932 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 28 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_013943

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13518
Approved symbol	CLIC4
Name	CLIC family member 4
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP566G223, CLIC4L, P64H1, H1, huH1, p64H1
Ensembl gene	ENSG00000169504
Ensembl biotype	protein_coding
OMIM	606536
Entrez	25932

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000374379, ENST00000488683, ENST00000489758, ENST00000497755, ENST00000889870, ENST00000951855

RefSeq mRNA: 1 — MANE Select: NM_013943 NM_013943

CCDS: CCDS256

Canonical transcript exons

ENST00000374379 — 6 exons

Exon	Start	End
ENSE00001129581	24839860	24840041
ENSE00001324395	24840773	24844321
ENSE00001463371	24745447	24745625
ENSE00003510823	24797742	24797851
ENSE00003512137	24814094	24814219
ENSE00003588080	24827010	24827116

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 218.5852 / max 2346.3974, expressed in 1806 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1435	179.8019	1787
1434	20.8621	1772
1436	5.9633	1487
1433	2.3128	1053
1450	1.7295	824
1446	1.3986	670
1454	1.3041	616
1447	0.9488	472
1453	0.8289	355
1452	0.8284	360

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood vessel layer	UBERON:0004797	99.67	gold quality
saphenous vein	UBERON:0007318	99.59	gold quality
cauda epididymis	UBERON:0004360	99.46	gold quality
popliteal artery	UBERON:0002250	99.39	gold quality
tibial artery	UBERON:0007610	99.39	gold quality
vena cava	UBERON:0004087	99.38	gold quality
aorta	UBERON:0000947	99.35	gold quality
descending thoracic aorta	UBERON:0002345	99.35	gold quality
thoracic aorta	UBERON:0001515	99.30	gold quality
smooth muscle tissue	UBERON:0001135	99.29	gold quality
ascending aorta	UBERON:0001496	99.28	gold quality
urethra	UBERON:0000057	99.26	gold quality
right coronary artery	UBERON:0001625	99.26	gold quality
trigeminal ganglion	UBERON:0001675	99.25	gold quality
cartilage tissue	UBERON:0002418	99.25	gold quality
calcaneal tendon	UBERON:0003701	99.23	gold quality
lower lobe of lung	UBERON:0008949	99.22	gold quality
pericardium	UBERON:0002407	99.18	gold quality
seminal vesicle	UBERON:0000998	99.15	gold quality
superficial temporal artery	UBERON:0001614	99.13	gold quality
left coronary artery	UBERON:0001626	99.10	gold quality
heart right ventricle	UBERON:0002080	99.09	gold quality
coronary artery	UBERON:0001621	99.08	gold quality
adult organism	UBERON:0007023	99.04	gold quality
mucosa of stomach	UBERON:0001199	98.98	gold quality
decidua	UBERON:0002450	98.96	gold quality
stromal cell of endometrium	CL:0002255	98.94	gold quality
dorsal root ganglion	UBERON:0000044	98.92	gold quality
parietal pleura	UBERON:0002400	98.88	gold quality
myometrium	UBERON:0001296	98.87	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	500.65
E-MTAB-9388	yes	374.70
E-MTAB-8142	yes	133.99
E-GEOD-84465	yes	27.80
E-MTAB-6678	yes	26.54
E-HCAD-11	yes	24.13
E-GEOD-135922	yes	22.64
E-MTAB-5061	yes	11.26
E-CURD-46	yes	10.66
E-GEOD-81547	yes	8.21
E-GEOD-83139	yes	6.97
E-MTAB-9543	yes	6.60
E-ENAD-27	yes	6.17
E-HCAD-25	yes	4.75
E-MTAB-10137	no	3.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, NKX3-1

miRNA regulators (miRDB)

155 targeting CLIC4, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-22-3P	99.93	68.13	917

Literature-anchored findings (GeneRIF, showing 40)

• CLIC4 is differentially regulated in fibroblasts and its expression contributes to a myofibroblast phenotype (PMID:12163372)
• CLIC4 has alternate cellular functions that are distinct from their proposed roles as chloride channels (PMID:14569596)
• subcellular localization of CLIC4 in endothelial cells was dependent on whether cells were engaged in proliferation or tube formation (PMID:16239224)
• up-regulation of mitochondrial CLIC4, together with a reduction in Bcl-2 and Bcl-xL, sensitizes Myc-expressing cells to the proapoptotic action of Bax. (PMID:16316993)
• preliminary crystallographic analysis (PMID:16842122)
• CLIC4 in tumor stroma has a role in myofibroblast conversion in human neoplasms (PMID:17200346)
• Nuclear CLIC4, possibly by altering the Cl(-) and pH of the nucleus, contributes to cell cycle arrest and the specific gene expression program associated with keratinocyte terminal differentiation. (PMID:17636002)
• Data showed that CLIC1 and CLIC5, but not CLIC4, were strongly and reversibly inhibited (or inactivated) by F-actin. (PMID:18028448)
• CLIC4 functions to promote endothelial cell proliferation and to regulate endothelial morphogenesis, and is thus involved in multiple steps of in vitro angiogenesis. (PMID:19247789)
• ROS-initiated CLIC4 up-regulation is required for TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiaton in ovarian cancer. (PMID:19639201)
• S100A4 and bone morphogenetic protein-2 codependently induce vascular smooth muscle cell migration via phospho-extracellular signal-regulated kinase and chloride intracellular channel 4. (PMID:19713532)
• Data suggest that CLIC4 is regulated by RhoA to be targeted to the plasma membrane, where it may function not as an inducible chloride channel but rather by displaying Cys-dependent transferase activity toward a yet unknown substrate. (PMID:19776349)
• CLIC4 may not be responsible for benign familial infantile seizures (BFIS) in a Chinese family affected with BFIS. (PMID:20374090)
• Reduced CLIC4 expression and nuclear residence detected in cancer cells is associated with the altered redox state of tumor cells and the absence of detectable nuclear CLIC4 in cancers contributes to TGF-beta resistance and enhances tumor development. (PMID:22387366)
• These results demonstrate that CLIC4 nuclear translocation is an integral part of the cellular response to starvation. (PMID:22761775)
• Our data indicate that CLIC4 protein may be a key element in the apoptotic response to oxidative stress. (PMID:23380911)
• CLIC4 increases tumor cell migration and invasion in a TGF-beta-dependent manner. (PMID:23416981)
• 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)
• This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. (PMID:24503901)
• Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension. (PMID:24503951)
• CLIC4, ERp29, and Smac/DIABLO integrated into a novel panel based on cancer stem-like cells in association with metastasis stratify the prognostic risks of colorectal cancer. (PMID:24916695)
• CLIC4 knockdown decreases cell-matrix adhesion, cell spreading and integrin signaling, whereas it increases cell motility. (PMID:25344254)
• 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)
• in malignant pleural mesothelioma, the gene expressions of CLIC3 and CLIC4 were significantly increased compared to controls (PMID:26445368)
• CLIC4 and Ihh could serve as biological markers for the progression, metastasis and/or invasiveness of pancreatic ductal adenocarcinoma. (PMID:28205343)
• High CLIC4 expression is associated with Merkel cell polyomavirus positive Merkel cell carcinoma. (PMID:29462791)
• Results provide evidence that the G4 structure formed in the CLIC4 promoter region may act as a regulatory element in regulating CLIC4 gene transcription. (PMID:30201851)
• These results suggest CLIC1 and CLIC4 are promising serum and tissue biomarkers as well as potential therapeutic targets for all EOC subtypes. This justifies development of high throughput serum/plasma biomarker assays to evaluate utility of a biomarker panel consisting of CLIC1, CLIC4 and CA125. (PMID:30282979)
• through profilin-1 binding, CLIC4 functions in a RhoA-mDia2-regulated signaling network to integrate cortical actin assembly and membrane protrusion (PMID:30381396)
• CLIC4 regulates late endosomal trafficking and matrix degradation activity of MMP14 at focal adhesions in RPE cells. (PMID:31439888)
• Cellular CLIC1 and CLIC4 are required for efficient Chikungunya virus replication. (PMID:31483794)
• CLIC4 abrogation promotes epithelial-mesenchymal transition in gastric cancer. (PMID:31560739)
• CLIC4 and CLIC1 bridge plasma membrane and cortical actin network for a successful cytokinesis. (PMID:31879279)
• Chloride intracellular channel 4 is dysregulated in endometrium of women with infertility and alters receptivity. (PMID:32807494)
• The intracellular chloride channel 4 (CLIC4) activates systemic sclerosis fibroblasts. (PMID:33331912)
• Astragaloside IV alleviates atherosclerosis through targeting circ_0000231/miR-135a-5p/CLIC4 axis in AS cell model in vitro. (PMID:33439448)
• Detection of Cells Displaying High Expression of CLIC4 in Tumor Tissue of Patients With Colorectal Cancer. (PMID:34697147)
• Characterization of chloride intracellular channel 4 in the regulation of human trophoblast function. (PMID:35078024)
• Circular RNA_0033596 aggravates endothelial cell injury induced by oxidized low-density lipoprotein via microRNA-217-5p /chloride intracellular channel 4 axis. (PMID:35081862)
• Induction of Pro-Fibrotic CLIC4 in Dermal Fibroblasts by TGF-beta/Wnt3a Is Mediated by GLI2 Upregulation. (PMID:35159339)

Cross-species orthologs

34 orthologs

Organism	Symbol	Gene ID
danio_rerio	clic4	ENSDARG00000022995
mus_musculus	Clic4	ENSMUSG00000037242
rattus_norvegicus	Clic4	ENSRNOG00000018109
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), CLIC3 (ENSG00000169583), CLIC1 (ENSG00000213719), EEF1G (ENSG00000254772), GSTT4 (ENSG00000276950)

Protein

Protein identifiers

Chloride intracellular channel protein 4 — Q9Y696 (reviewed: Q9Y696)

Alternative names: Glutaredoxin-like oxidoreductase CLIC4, Intracellular chloride ion channel protein p64H1

All UniProt accessions (2): Q9Y696, Q6FIC5

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. 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. Has alternate cellular functions like a potential role in angiogenesis or in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis. Could also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis). Promotes cell-surface expression of HRH3.

Subunit / interactions. Component of a multimeric complex consisting of several cytoskeletal proteins, including actin, ezrin, alpha-actinin, gelsolin, IQGAP1 and CLIC5A. Binds directly to brain dynamin I in a complex containing actin, tubulin and 14-3-3 isoforms. Monomer. Interacts with HRH3. Interacts with AKAP9.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cytoplasmic vesicle membrane. Nucleus. Cell membrane. Mitochondrion. Cell junction. Endoplasmic reticulum membrane.

Tissue specificity. Detected in epithelial cells from colon, esophagus and kidney (at protein level). Expression is prominent in heart, kidney, placenta and skeletal muscle.

Activity regulation. Inhibited by rapamycin, amphotericin B and 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 chloride 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.

Induction. Up-regulated by calcium ions in differentiating keratinocytes. Up-regulated in myofibroblasts.

Similarity. Belongs to the chloride channel CLIC family.

RefSeq proteins (1): NP_039234* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002946	CLIC	Family
IPR010987	Glutathione-S-Trfase_C-like	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: PF22441

Catalyzed reactions (Rhea), 7 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• choline(out) = choline(in) (RHEA:32751)
• 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 (38 total): helix 11, modified residue 8, strand 6, sequence conflict 4, turn 3, initiator methionine 1, chain 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2AHE	X-RAY DIFFRACTION	1.8
3OQS	X-RAY DIFFRACTION	2
2D2Z	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y696-F1	91.97	0.80

Functional residue map

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

Post-translational modifications (8): 132, 167, 236, 244, 2, 4, 24, 130

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 484 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_GROWTH, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, TGACCTY_ERR1_Q2, AMIT_SERUM_RESPONSE_40_MCF10A, MODULE_503

GO Biological Process (17): angiogenesis (GO:0001525), endothelial cell morphogenesis (GO:0001886), chloride transport (GO:0006821), vacuolar acidification (GO:0007035), fertilization (GO:0009566), cell differentiation (GO:0030154), keratinocyte differentiation (GO:0030216), negative regulation of cell migration (GO:0030336), establishment or maintenance of apical/basal cell polarity (GO:0035088), multicellular organism growth (GO:0035264), branching morphogenesis of an epithelial tube (GO:0048754), regulation of cytoskeleton organization (GO:0051493), retina vasculature morphogenesis in camera-type eye (GO:0061299), cellular response to calcium ion (GO:0071277), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), chloride transmembrane transport (GO:1902476)

GO Molecular Function (3): chloride channel activity (GO:0005254), oxidoreductase activity (GO:0016491), protein binding (GO:0005515)

GO Cellular Component (25): cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum membrane (GO:0005789), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), microvillus (GO:0005902), cell-cell junction (GO:0005911), cell surface (GO:0009986), actin cytoskeleton (GO:0015629), membrane (GO:0016020), nuclear matrix (GO:0016363), midbody (GO:0030496), cytoplasmic vesicle membrane (GO:0030659), chloride channel complex (GO:0034707), apical part of cell (GO:0045177), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), cytoskeleton (GO:0005856), microtubule cytoskeleton (GO:0015630), cytoplasmic vesicle (GO:0031410), monoatomic ion channel complex (GO:0034702), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
cytoplasm	4
intracellular membrane-bounded organelle	3
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
endothelial cell development	1
epithelial cell morphogenesis	1
monoatomic anion transport	1
inorganic anion transport	1
intracellular pH reduction	1
sexual reproduction	1
reproductive process	1
cellular developmental process	1
epidermal cell differentiation	1
skin development	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
establishment or maintenance of bipolar cell polarity	1
multicellular organismal process	1
developmental growth	1
tube morphogenesis	1
epithelial tube morphogenesis	1
morphogenesis of a branching epithelium	1
cytoskeleton organization	1
regulation of organelle organization	1
anatomical structure morphogenesis	1
retina vasculature development in camera-type eye	1
response to calcium ion	1
cellular response to metal ion	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
catalytic activity	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1296 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLIC4	HIVEP2	P31629	896
CLIC4	HRH3	Q9Y5N1	770
CLIC4	PPM1A	P35813	750
CLIC4	SMAD3	P84022	706
CLIC4	CLCN4	P51793	683
CLIC4	PHC3	Q8NDX5	682
CLIC4	EZR	P15311	673
CLIC4	SLC16A8	O95907	629
CLIC4	HIVEP1	P15822	588
CLIC4	AQP1	P29972	558
CLIC4	SMAD2	Q15796	535
CLIC4	MYC	P01106	527
CLIC4	CAV1	Q03135	464
CLIC4	DNM1	Q05193	460
CLIC4	TGFB1	P01137	445

IntAct

25 interactions, top by confidence:

A	B	Type	Score
TPRN	CLIC4	psi-mi:“MI:0915”(physical association)	0.670
CLIC4	CLIC2	psi-mi:“MI:0914”(association)	0.530
Kpna2	CLIC4	psi-mi:“MI:0407”(direct interaction)	0.440
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	CLIC4	psi-mi:“MI:0915”(physical association)	0.370
CLIC4	REL	psi-mi:“MI:0915”(physical association)	0.370
Cdc16	ANAPC15	psi-mi:“MI:0914”(association)	0.350
Anapc16	ANAPC15	psi-mi:“MI:0914”(association)	0.350
MAPT	LANCL1	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
GATD3	NME1	psi-mi:“MI:0914”(association)	0.350
GATD3	NDUFS2	psi-mi:“MI:0914”(association)	0.350
EGFR	ENO1	psi-mi:“MI:0914”(association)	0.350
SAR1B	UBA6	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
CACYBP	PSMD11	psi-mi:“MI:0914”(association)	0.350
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270
	HLA-B	psi-mi:“MI:2364”(proximity)	0.270
MCC	CLIC4	psi-mi:“MI:0915”(physical association)	0.000
CLIC4	TPRN	psi-mi:“MI:0915”(physical association)	0.000
CLIC6	CLIC4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (161): CLIC2 (Affinity Capture-MS), CLIC6 (Affinity Capture-MS), CLIC5 (Affinity Capture-MS), TPRN (Affinity Capture-MS), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation), CLIC4 (Co-fractionation)

ESM2 similar proteins: A0A1U8QXK4, A8XWD1, O00299, O15247, O45405, O45503, O62471, O64471, O95833, P14693, P34599, Q03606, Q08BC6, Q0II26, Q13155, Q22949, Q29LT4, Q32PX2, Q4VBW0, Q5E9B7, Q5M883, Q5R957, Q6DF78, Q6MG61, Q6NRQ2, Q7YTB0, Q8BXK9, Q8R010, Q8T773, Q8WQA4, Q95MF9, Q99K01, Q9CAS6, Q9D7P7, Q9EPT8, Q9HE00, Q9QYB1, Q9TYN3, Q9UGL1, Q9V8W3

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, Q8WQA4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CDK5	“up-regulates quantity by stabilization”	CLIC4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	19
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
599503	NM_013943.3(CLIC4):c.220C>T (p.His74Tyr)	Likely pathogenic

SpliceAI

1719 predictions. Top by Δscore:

Variant	Effect	Δscore
1:24745626:G:GA	donor_loss	1.0000
1:24745626:G:GG	donor_gain	1.0000
1:24797737:TCCA:T	acceptor_loss	1.0000
1:24797738:CCA:C	acceptor_loss	1.0000
1:24797739:CAG:C	acceptor_loss	1.0000
1:24797740:AGG:A	acceptor_loss	1.0000
1:24797740:AGGCT:A	acceptor_gain	1.0000
1:24797741:GGCTG:G	acceptor_gain	1.0000
1:24797847:AAAAG:A	donor_loss	1.0000
1:24797848:AAAGG:A	donor_loss	1.0000
1:24797849:AAGGT:A	donor_loss	1.0000
1:24797852:G:C	donor_loss	1.0000
1:24797853:T:G	donor_loss	1.0000
1:24814088:CAACA:C	acceptor_loss	1.0000
1:24814092:A:AG	acceptor_gain	1.0000
1:24814092:AG:A	acceptor_gain	1.0000
1:24814093:G:GG	acceptor_gain	1.0000
1:24814093:GG:G	acceptor_gain	1.0000
1:24814093:GGA:G	acceptor_gain	1.0000
1:24814093:GGAA:G	acceptor_gain	1.0000
1:24814215:CCCAA:C	donor_gain	1.0000
1:24814216:CCAA:C	donor_gain	1.0000
1:24814217:CAA:C	donor_gain	1.0000
1:24814218:AA:A	donor_gain	1.0000
1:24814220:G:GG	donor_gain	1.0000
1:24814220:G:T	donor_loss	1.0000
1:24814221:TGA:T	donor_loss	1.0000
1:24814222:GAG:G	donor_loss	1.0000
1:24814223:AG:A	donor_loss	1.0000
1:24814232:GAAAA:G	donor_gain	1.0000

AlphaMissense

1688 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:24745615:T:C	L21P	1.000
1:24797766:G:A	G33R	1.000
1:24797766:G:C	G33R	1.000
1:24797767:G:A	G33E	1.000
1:24797767:G:T	G33V	1.000
1:24797772:T:C	C35R	1.000
1:24797774:C:G	C35W	1.000
1:24797778:T:C	F37L	1.000
1:24797780:T:A	F37L	1.000
1:24797780:T:G	F37L	1.000
1:24797788:G:T	R40M	1.000
1:24797793:T:C	F42L	1.000
1:24797795:C:A	F42L	1.000
1:24797795:C:G	F42L	1.000
1:24797803:T:C	L45P	1.000
1:24797823:T:C	F52L	1.000
1:24797825:T:A	F52L	1.000
1:24797825:T:G	F52L	1.000
1:24797839:T:A	V57D	1.000
1:24814108:T:C	L66P	1.000
1:24814126:G:A	G72E	1.000
1:24814135:C:A	P75Q	1.000
1:24814137:C:T	P76S	1.000
1:24814138:C:A	P76Q	1.000
1:24814140:T:C	F77L	1.000
1:24814142:T:A	F77L	1.000
1:24814142:T:G	F77L	1.000
1:24827054:G:A	G118E	1.000
1:24827065:T:C	F122L	1.000
1:24827067:T:A	F122L	1.000

dbSNP variants (sampled 300 via entrez): RS1000013824 (1:24759317 T>C,G), RS1000014631 (1:24764577 C>A), RS1000016406 (1:24804557 ATG>A), RS1000195705 (1:24765573 G>C), RS1000220400 (1:24816014 C>T), RS1000236815 (1:24752566 A>G), RS1000255797 (1:24807065 A>C), RS1000264186 (1:24817071 C>A), RS1000317803 (1:24772711 C>T), RS1000417991 (1:24778899 A>G), RS1000429275 (1:24824297 C>G), RS1000430636 (1:24768030 G>A,C), RS1000452426 (1:24813338 G>A,T), RS1000453017 (1:24826370 G>A), RS1000494395 (1:24765973 G>A)

Disease associations

OMIM: gene MIM:606536 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000817_151	Height	2.000000e-12
GCST005168_2	Systolic blood pressure	1.000000e-06
GCST006661_182	Male-pattern baldness	1.000000e-10
GCST006661_258	Male-pattern baldness	5.000000e-21
GCST006979_867	Heel bone mineral density	1.000000e-13
GCST90000025_907	Appendicular lean mass	2.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067411 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.27	Kd	53.36	nM	CHEMBL5653589
7.27	ED50	53.36	nM	CHEMBL5653589
6.62	Kd	237.4	nM	CHEMBL3752910
6.62	ED50	237.4	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148081: Binding affinity to human CLIC4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0534	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148081: Binding affinity to human CLIC4 incubated for 45 mins by Kinobead based pull down assay	kd	0.2374	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
sodium arsenite	increases expression, affects expression, decreases expression	4
bisphenol A	affects cotreatment, decreases expression, increases expression	3
Smoke	decreases expression, increases abundance	3
cobaltous chloride	decreases expression, increases expression	2
entinostat	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Arsenic Trioxide	increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	increases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
tributyltin	increases expression	1
trichostatin A	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression, decreases reaction	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
didecyldimethylammonium	increases expression	1
nickel sulfate	increases expression	1
methylmercury II	increases expression	1
beta-methylcholine	affects 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
CHEMBL5651123	Binding	Binding affinity to human CLIC4 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.