CLIC6

Summary

CLIC6 (CLIC family member 6, HGNC:2065) is a protein-coding gene on chromosome 21q22.12, encoding Chloride intracellular channel protein 6 (Q96NY7). In the soluble state, catalyzes glutaredoxin-like thiol disulfide exchange reactions with reduced glutathione as electron donor.

This gene encodes a member of the chloride intracellular channel family of proteins. The gene is part of a large triplicated region found on chromosomes 1, 6, and 21. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 54102 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 183 total — 6 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 40 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.45 (unconstrained)
• MANE Select transcript: NM_053277
• Notable: 183 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2065
Approved symbol	CLIC6
Name	CLIC family member 6
Location	21q22.12
Locus type	gene with protein product
Status	Approved
Aliases	CLIC5
Ensembl gene	ENSG00000159212
Ensembl biotype	protein_coding
OMIM	615321
Entrez	54102

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

MANE Select: ENST00000349499

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2

ENST00000349499, ENST00000360731, ENST00000954659, ENST00001131812

RefSeq mRNA: 2 — MANE Select: NM_053277 NM_001317009, NM_053277

CCDS: CCDS13638, CCDS82669

Canonical transcript exons

ENST00000349499 — 6 exons

Exon	Start	End
ENSE00001044021	34708700	34708806
ENSE00001044034	34709357	34709538
ENSE00001044048	34707944	34708069
ENSE00002449170	34707280	34707389
ENSE00003904437	34668994	34670762
ENSE00003907791	34716321	34718223

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 99.52.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6413 / max 231.3026, expressed in 295 samples.

Highest expression (Bgee): pigmented layer of retina, bronchial epithelial cell, bronchus, nasal cavity epithelium, caput epididymis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CLIC6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 40 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 40 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Muscularis	eqtl	4.4e-50	+0.98	21:34683596:G:A
Lung	eqtl	3.1e-42	+0.55	21:34683596:G:A
Adipose Subcutaneous	eqtl	1.1e-37	+0.42	21:34687310:C:T
Nerve Tibial	eqtl	3.5e-32	+0.37	21:34687310:C:T
Pituitary	eqtl	1.2e-26	+0.72	21:34702351:C:T
Esophagus Gastroesophageal Junction	eqtl	1.4e-25	+0.84	21:34690229:G:T
Skin Sun Exposed Lower leg	eqtl	2.4e-20	-0.25	21:34688369:C:G
Adipose Visceral Omentum	eqtl	7.3e-19	+0.45	21:34687310:C:T
Colon Transverse	eqtl	1.4e-16	-0.46	21:34678939:G:A
Brain Cerebellar Hemisphere	eqtl	3.2e-15	+0.84	21:34690638:T:C
Esophagus Mucosa	eqtl	1.0e-13	+0.37	21:34683596:G:A
Colon Sigmoid	eqtl	1.3e-13	+0.61	21:34683596:G:A
Brain Cerebellum	eqtl	3.5e-12	+0.62	21:34690638:T:C
Brain Putamen basal ganglia	eqtl	5.9e-12	+0.79	21:34690402:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.3e-11	-0.23	21:34688369:C:G
Artery Tibial	eqtl	3.6e-11	+0.24	21:34687310:C:T
Muscle Skeletal	eqtl	4.9e-11	+0.27	21:34687310:C:T
Breast Mammary Tissue	eqtl	4.6e-10	-0.33	21:34700263:C:A
Heart Left Ventricle	eqtl	1.9e-09	-0.36	21:34700263:C:A
Minor Salivary Gland	eqtl	6.4e-09	-0.37	21:34662811:C:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
188937	1.4885	277
188935	0.0919	47
188936	0.0609	21

Top tissues by expression

showing 100 of 237 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.52	gold quality
bronchial epithelial cell	CL:0002328	99.44	gold quality
bronchus	UBERON:0002185	98.89	gold quality
nasal cavity epithelium	UBERON:0005384	98.86	gold quality
caput epididymis	UBERON:0004358	97.63	gold quality
palpebral conjunctiva	UBERON:0001812	95.18	gold quality
epithelium of nasopharynx	UBERON:0001951	94.92	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.38	gold quality
nasal cavity mucosa	UBERON:0001826	94.12	gold quality
epithelial cell of pancreas	CL:0000083	93.59	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	93.57	gold quality
pancreatic ductal cell	CL:0002079	91.14	silver quality
cardia of stomach	UBERON:0001162	90.66	gold quality
body of stomach	UBERON:0001161	89.41	gold quality
visceral pleura	UBERON:0002401	89.04	gold quality
trachea	UBERON:0003126	88.92	gold quality
stomach	UBERON:0000945	88.20	gold quality
urethra	UBERON:0000057	87.87	gold quality
parotid gland	UBERON:0001831	87.47	gold quality
fundus of stomach	UBERON:0001160	86.94	gold quality
amniotic fluid	UBERON:0000173	86.61	gold quality
right uterine tube	UBERON:0001302	85.99	gold quality
pylorus	UBERON:0001166	85.44	gold quality
minor salivary gland	UBERON:0001830	84.73	gold quality
ileal mucosa	UBERON:0000331	84.18	gold quality
saliva-secreting gland	UBERON:0001044	83.86	gold quality
lower lobe of lung	UBERON:0008949	83.80	silver quality
cardiac muscle of right atrium	UBERON:0003379	81.66	silver quality
apex of heart	UBERON:0002098	81.58	gold quality
mouth mucosa	UBERON:0003729	79.71	gold quality
gall bladder	UBERON:0002110	79.58	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.32	gold quality
cerebellar vermis	UBERON:0004720	79.27	silver quality
tibialis anterior	UBERON:0001385	79.26	silver quality
left ventricle myocardium	UBERON:0006566	79.02	silver quality
thyroid gland	UBERON:0002046	78.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.77	gold quality
left lobe of thyroid gland	UBERON:0001120	78.65	gold quality
urinary bladder	UBERON:0001255	78.48	gold quality
seminal vesicle	UBERON:0000998	78.26	gold quality
corpus epididymis	UBERON:0004359	77.90	gold quality
right lobe of thyroid gland	UBERON:0001119	77.40	gold quality
calcaneal tendon	UBERON:0003701	76.53	gold quality
heart left ventricle	UBERON:0002084	76.51	gold quality
prostate gland	UBERON:0002367	76.24	gold quality
cardiac ventricle	UBERON:0002082	76.15	gold quality
lung	UBERON:0002048	75.58	gold quality
mucosa of sigmoid colon	UBERON:0004993	75.55	gold quality
right lung	UBERON:0002167	75.42	gold quality
skin of hip	UBERON:0001554	75.32	gold quality
right atrium auricular region	UBERON:0006631	75.24	gold quality
cardiac atrium	UBERON:0002081	75.12	gold quality
upper leg skin	UBERON:0004262	74.87	gold quality
colonic mucosa	UBERON:0000317	74.23	gold quality
islet of Langerhans	UBERON:0000006	74.09	gold quality
fallopian tube	UBERON:0003889	74.07	gold quality
oviduct epithelium	UBERON:0004804	74.07	gold quality
tibia	UBERON:0000979	73.73	gold quality
upper lobe of lung	UBERON:0008948	73.59	gold quality
tendon	UBERON:0000043	73.50	gold quality
myocardium	UBERON:0002349	73.38	silver quality
heart	UBERON:0000948	73.32	gold quality
adipose tissue	UBERON:0001013	72.98	gold quality
skin of leg	UBERON:0001511	72.87	gold quality
upper lobe of left lung	UBERON:0008952	72.85	gold quality
vermiform appendix	UBERON:0001154	72.65	gold quality
right coronary artery	UBERON:0001625	71.83	gold quality
kidney epithelium	UBERON:0004819	71.66	gold quality
zone of skin	UBERON:0000014	71.35	gold quality
vagina	UBERON:0000996	70.81	gold quality
skin of abdomen	UBERON:0001416	70.74	gold quality
oral cavity	UBERON:0000167	70.65	gold quality
caecum	UBERON:0001153	70.50	gold quality
mucosa of transverse colon	UBERON:0004991	70.35	gold quality
adenohypophysis	UBERON:0002196	70.12	gold quality
endocervix	UBERON:0000458	70.04	gold quality
thoracic mammary gland	UBERON:0005200	69.88	gold quality
mammary gland	UBERON:0001911	69.87	gold quality
transverse colon	UBERON:0001157	69.30	gold quality
left ovary	UBERON:0002119	69.28	gold quality
pancreas	UBERON:0001264	69.24	gold quality
cauda epididymis	UBERON:0004360	68.93	silver quality
hindlimb stylopod muscle	UBERON:0004252	68.92	gold quality
layer of synovial tissue	UBERON:0007616	68.71	gold quality
rectum	UBERON:0001052	68.51	gold quality
right ovary	UBERON:0002118	68.08	gold quality
heart right ventricle	UBERON:0002080	67.97	silver quality
deltoid	UBERON:0001476	67.76	silver quality
mucosa of stomach	UBERON:0001199	67.74	gold quality
left coronary artery	UBERON:0001626	67.54	gold quality
tonsil	UBERON:0002372	67.49	gold quality
tibial nerve	UBERON:0001323	67.44	gold quality
coronary artery	UBERON:0001621	66.72	gold quality
parietal pleura	UBERON:0002400	66.67	gold quality
colon	UBERON:0001155	66.46	gold quality
body of pancreas	UBERON:0001150	66.37	gold quality
large intestine	UBERON:0000059	66.31	gold quality
metanephros cortex	UBERON:0010533	66.31	gold quality
left uterine tube	UBERON:0001303	65.94	gold quality
tendon of biceps brachii	UBERON:0008188	65.91	silver quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	309.11
E-GEOD-135922	yes	15.78
E-ANND-3	yes	5.46

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	505.7
Stomach 1	tissue	86.1	medium
Parathyroid gland	tissue	26.6	not detected
Superior colliculi	tissue	22.1
Medulla oblongata	tissue	19.2
Cervix	tissue	14.9	low
Caudate putamen	tissue	13.7
Hippocampal formation	tissue	12.9
Thyroid gland	tissue	12.4	not detected
Septum	tissue	12.2
Urinary bladder	tissue	12.0	low
Thalamus	tissue	11.5
Fallopian tube	tissue	10.7	medium
Heart muscle	tissue	10.3	not detected
Breast	tissue	9.8	medium
Lung	tissue	9.2	not detected
Cerebral cortex	tissue	8.8	not detected
Occipital cortex	tissue	8.8
Salivary gland	tissue	8.6	medium
Gallbladder	tissue	8.3	not detected
Thymus	tissue	7.9
Substantia nigra	tissue	7.8
Cerebellum	tissue	7.4	not detected
Entorhinal cortex	tissue	6.9
Retrosplenial cortex	tissue	6.9
Prostate	tissue	6.8	medium
Amygdala	tissue	6.7
Somatosensory cortex	tissue	6.7
Seminal vesicle	tissue	6.6	low
Basal ganglia	tissue	6.2	low
Olfactory bulb	tissue	6.2
Retrosplenial and cingulate cortex	tissue	6.1
Temporal cortex	tissue	6.0
Corpus callosum	tissue	5.8
Motor cortex	tissue	5.7
Midbrain	tissue	5.5
Ventral forebrain	tissue	5.5
Insular cortex	tissue	5.4
Prefrontal cortex	tissue	5.3
Periaqueductal gray	tissue	5.2
Ovary	tissue	5.1	not detected
Hypothalamus	tissue	5.0
Vagina	tissue	4.8	not detected
Putamen	tissue	4.4
Pons	tissue	4.1
Tongue	tissue	4.1
Appendix	tissue	4.1	low
Tonsil	tissue	3.6	not detected
Colon	tissue	3.4	not detected
Spinal cord	tissue	3.3
Pituitary gland	tissue	3.1
Hippocampus	tissue	2.8	medium
Rectum	tissue	2.7	medium
Epididymis	tissue	2.5	not detected
Endometrium 1	tissue	2.0	medium
Duodenum	tissue	1.9	not detected
Locus coeruleus	tissue	1.9
Postcentral gyrus	tissue	1.9
Pancreas	tissue	1.7	medium
Nucleus accumbens	tissue	1.6

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Hippocampus, CA3 (24.6), Subiculum (12.9), Periaquaductal grey, lateral (10.8), Habenula (9.7), Nucleus tractus solitarii (7.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CLIC6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 75 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7161-5P	99.68	68.92	1592

Functional genomics

gnomAD constraint: pLI 7.85e-14, LOEUF 1.45, missense Z -2.63 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000349499 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
21:34,669,389–34,669,938	284 / 278.6	1.02	no
21:34,669,939–34,670,145	57 / 117.6	0.48	no
21:34,670,146–34,716,479	647 / 596.9	1.08	no

Cross-species orthologs

24 orthologs

Organism	Symbol	Gene ID
danio_rerio	clic6	ENSDARG00000099108
mus_musculus	Clic6	ENSMUSG00000022949
rattus_norvegicus	Clic6	ENSRNOG00000026870
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	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), CLIC4 (ENSG00000169504), CLIC3 (ENSG00000169583), CLIC1 (ENSG00000213719), EEF1G (ENSG00000254772), GSTT4 (ENSG00000276950)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2146607) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal uterus morphology	1
abnormal startle reflex	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Sus scrofa	Q29238	100.0%	Diamond
Bos taurus	Q5E9B7	100.0%	Diamond
Pongo abelii	Q5R957	99.2%	Diamond
Oryctolagus cuniculus	Q95MF9	98.2%	Diamond
Arabidopsis thaliana	Q9FRL8	75.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
RUNX1-AS1	ncRNA	124905014
LINC00160	ncRNA	54064
RUNX1-IT1	ncRNA	80215
RUNX1	protein-coding	861
LINC01426	ncRNA	100506385
RCAN1	protein-coding	1827
KCNE1	protein-coding	3753
SMIM34	protein-coding	388820
C21orf140	protein-coding	101928147

Protein

Protein identifiers

Chloride intracellular channel protein 6 — Q96NY7 (reviewed: Q96NY7)

Alternative names: Glutaredoxin-like oxidoreductase CLIC6, Parchorin

All UniProt accessions (1): Q96NY7

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 chloride-selective channels. The channel opens upon membrane depolarization at positive voltages and closes at negative membrane voltages. May play a critical role in water-secreting cells, possibly through the regulation of chloride ion transport.

Subunit / interactions. Monomer (soluble state). Interacts with dopamine receptors DRD2, DRD3 and DRD4.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in brain, placenta, pancreas, liver, lung, heart, kidney, liver, spleen, soleus muscle, and brown fat.

Post-translational modifications. Phosphorylated.

Activity regulation. Channel activity is redox- and pH-regulated. 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 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.

Similarity. Belongs to the chloride channel CLIC family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96NY7-1	B	yes
Q96NY7-2	A

RefSeq proteins (2): NP_001303938, NP_444507* (*=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)

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (34 total): repeat 13, compositionally biased region 9, modified residue 3, region of interest 2, chain 1, transmembrane region 1, domain 1, short sequence motif 1, splice variant 1, sequence variant 1, mutagenesis site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NY7-F1	60.24	0.19

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted intracellular proteins, UniProt - Evidence at transcript level

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

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 (3)

Type	Positions
Phosphoserine	44, 397, 442

Mutagenesis-validated functional residues (1)

Position	Phenotype
648	decreases channel conductance and abolishes its dependence on ph.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 280 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, LFA1_Q6, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_INORGANIC_ANION_TRANSPORT, GOCC_MICROTUBULE_ORGANIZING_CENTER, GTGCCTT_MIR506, GOBP_CHLORIDE_TRANSPORT, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOCC_CENTROSOME, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_MULTI_MULTICELLULAR_ORGANISM_PROCESS, GOCC_APICAL_PLASMA_MEMBRANE

GO Biological Process (4): monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), chloride transmembrane transport (GO:1902476)

GO Molecular Function (5): chloride channel activity (GO:0005254), oxidoreductase activity (GO:0016491), D2 dopamine receptor binding (GO:0031749), D3 dopamine receptor binding (GO:0031750), D4 dopamine receptor binding (GO:0031751)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), chloride channel complex (GO:0034707), extracellular exosome (GO:0070062), monoatomic ion channel complex (GO:0034702)

GO top-level categories

18 GO namespaces:

Category	Terms
dopamine receptor binding	3
transport	1
monoatomic anion transport	1
inorganic anion 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
intracellular anatomical structure	1
cellular anatomical structure	1
membrane	1
cell periphery	1
monoatomic ion channel complex	1
extracellular vesicle	1
transmembrane transporter complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
extracellular exosome	CC	high-throughput assay
chloride channel activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 872 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLIC6	TMC1	Q8TDI8	514
CLIC6	TPRN	Q4KMQ1	497
CLIC6	ADGRV1	Q8WXG9	465
CLIC6	SLC26A5	P58743	457
CLIC6	GRXCR2	A6NFK2	438
CLIC6	TMC2	Q8TDI7	405
CLIC6	MYO7A	P78427	404
CLIC6	WFS1	O76024	370
CLIC6	STOX1	Q6ZVD7	370
CLIC6	SLC17A8	Q8NDX2	370
CLIC6	PCGF3	Q3KNV8	370
CLIC6	RPGRIP1L	Q68CZ1	370
CLIC6	SLC52A3	Q9NQ40	370
CLIC6	CLCA2	Q9UQC9	370
CLIC6	COCH	O43405	369

IntAct

Human interaction partners of CLIC6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

24 partners by confidence:

Partner	Interaction type	MIscore	Records
ACTB	physical association	0.000	1
ALDH5A1	physical association	0.000	1
ARG2	physical association	0.000	1
ATRX	physical association	0.000	1
CLIC4	physical association	0.000	1
EEF1A1	physical association	0.000	1
FCGR1A	physical association	0.000	1
GFPT2	physical association	0.000	1
HUWE1	physical association	0.000	1
LGI1	physical association	0.000	1
MYO1E	physical association	0.000	1
NFE2L2	physical association	0.000	1
NISCH	physical association	0.000	1
OXR1	physical association	0.000	1
PGK1	physical association	0.000	1
PKM	physical association	0.000	1
PPRC1	physical association	0.000	1
TAF12	physical association	0.000	1
TUBGCP5	physical association	0.000	1
UBE4A	physical association	0.000	1
ZNF18	physical association	0.000	1
ZNF224	physical association	0.000	1
ZNF234	physical association	0.000	1
ZNF439	physical association	0.000	1

BioGRID (34 interactions; top human partners by supporting records): CLIC4 (Affinity Capture-MS; 4 records), DRD3 (Two-hybrid; 2 records), ACTB (Two-hybrid), ALDH5A1 (Two-hybrid), ARG2 (Two-hybrid), ATRX (Two-hybrid), CLIC5 (Affinity Capture-MS), DRD2 (Two-hybrid), DRD4 (Two-hybrid), EEF1A1 (Two-hybrid), FCGR1A (Two-hybrid), GFPT2 (Two-hybrid), HUWE1 (Two-hybrid), LGI1 (Two-hybrid), MYO1E (Two-hybrid)

Disease & clinical

Genetic variants

Variant evidence for CLIC6: 183 ClinVar records (7 pathogenic / likely pathogenic); 6 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	140
Likely benign	21
Benign	10

Top pathogenic / likely-pathogenic (7)

Showing all 7 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
812913	NC_000021.8:g.35304341_36865875del	Pathogenic	reviewed by expert panel	2
59248	GRCh37/hg19 21q22.1(chr21:35292816-36834601)x3	Pathogenic	criteria provided, single submitter	1
1321998	GRCh37/hg19 21p13-q22.3(chr21:1-48129895)x3	Pathogenic	criteria provided, single submitter	1
2424231	NC_000021.8:g.(?36079578)(37133458_?)del	Pathogenic	criteria provided, single submitter	1
4682976	GRCh37/hg19 21q22.11-22.12(chr21:35298071-36876005)x1	Pathogenic	criteria provided, single submitter	1
4686718	GRCh38/hg38 21q22.11-22.12(chr21:33875015-34972115)x1	Likely pathogenic	criteria provided, single submitter	1
685844	GRCh37/hg19 21q22.11-22.12(chr21:35298070-36876005)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore CLIC6’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 476):

Position(s)	Effect	Δscore	Sites
21:34716319–34716320	acceptor_loss	1.0000	6
21:34708070–34708071	donor_loss	0.9900	5
21:34708698	acceptor_gain	0.9900
21:34709355–34709356	acceptor_loss	0.9900	6
21:34709469	donor_gain	0.9900
21:34708698–34708699	acceptor_loss	0.9800	5
21:34708807–34708808	donor_loss	0.9800	5
21:34708811	donor_loss	0.9800	2
21:34709349	acceptor_gain	0.9800
21:34670763–34670764	donor_loss	0.9700	5

AlphaMissense

1,112 missense substitutions predicted likely pathogenic (of 4,493 scored), across 210 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M495	9	0.940	0.995
D640	8	0.996	0.999
F574	8	0.993	1.000
F504	8	0.990	0.999
F494	8	0.989	0.999
F529	8	0.987	0.999
D539	8	0.986	0.996
F577	8	0.986	0.999
F489	8	0.985	0.999
D510	8	0.984	0.996
F682	8	0.965	0.998
D480	8	0.958	0.976
H648	8	0.956	0.994
N583	8	0.952	0.994
D632	8	0.948	0.985
F660	8	0.946	0.995
F532	8	0.924	0.996
D572	8	0.919	0.977
N486	8	0.899	0.995
D517	8	0.889	0.945

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Lung Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	favorable	4.85e-05
Breast Invasive Carcinoma (TCGA)	favorable	0.00011
Glioblastoma Multiforme (validation)	unfavorable	0.00012
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000639

Disease associations

OMIM: gene MIM:615321 | disease phenotypes: MIM:601399

GenCC curated gene-disease

Mondo (3): hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (MONDO:0100083), thrombocytopenia (MONDO:0002049), hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Orphanet (1): Familial platelet disorder with associated myeloid malignancy (Orphanet:71290)

GWAS associations

6 associations:

Study	Trait	p-value
GCST009798_20	Asthma	5e-11
GCST009665_21	Breast cancer	2e-9
GCST007009_8	Hippocampal volume	2e-7
GCST002874_7	Psoriasis	1e-6
GCST008159_62	Waist-to-hip ratio adjusted for BMI	6e-6
GCST008748_4	Epigenetic age acceleration in alcohol use disorder	8e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0005035	hippocampal volume
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0000473	epigenetic status
EFO:0022597	aging

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C563324	Platelet Disorder, Familial, with Associated Myeloid Malignancy *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression	8
methylmercuric chloride	increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
entinostat	increases expression, affects cotreatment	2
Decitabine	decreases expression, decreases reaction, affects expression	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Smoke	decreases expression, decreases reaction	2
bisphenol F	increases methylation	1
bisphenol A	increases expression	1
terbufos	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	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
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects expression	1
Fonofos	increases methylation	1
Estradiol	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Parathion	increases methylation	1
Polychlorinated Biphenyls	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Genistein	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

6 trials:

NCT	Phase	Status	Title
NCT03600649	Phase 1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05266196	Phase 1/2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	Phase 1/2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	Phase 1/2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis
NCT03854318	Not specified	RECRUITING	Longitudinal Studies of Patient With FPDMM