CLIC5

Summary

CLIC5 (CLIC family member 5, HGNC:13517) is a protein-coding gene on chromosome 6p21.1, encoding Chloride intracellular channel protein 5 (Q9NZA1). 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 (CLIC) family of chloride ion channels. The encoded protein associates with actin-based cytoskeletal structures and may play a role in multiple processes including hair cell stereocilia formation, myoblast proliferation and glomerular podocyte and endothelial cell maintenance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 53405 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive (Supportive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 213 total — 4 pathogenic, 2 likely-pathogenic
• MANE Select transcript: NM_016929

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13517
Approved symbol	CLIC5
Name	CLIC family member 5
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	DFNB102
Ensembl gene	ENSG00000112782
Ensembl biotype	protein_coding
OMIM	607293
Entrez	53405

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding_CDS_not_defined, 6 protein_coding, 1 nonsense_mediated_decay

ENST00000185206, ENST00000339561, ENST00000464137, ENST00000476852, ENST00000484572, ENST00000486570, ENST00000487396, ENST00000544153, ENST00000642250, ENST00000643162, ENST00000644324, ENST00000644878, ENST00000645626, ENST00000672327

RefSeq mRNA: 5 — MANE Select: NM_016929 NM_001114086, NM_001256023, NM_001370649, NM_001370650, NM_016929

CCDS: CCDS47438, CCDS4914, CCDS59022

Canonical transcript exons

ENST00000339561 — 6 exons

Exon	Start	End
ENSE00000481266	45914228	45914409
ENSE00000754663	45941547	45941653
ENSE00000754665	45949256	45949381
ENSE00001408953	46015480	46015860
ENSE00002536488	45955135	45955244
ENSE00003720446	45898456	45903255

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 99.73.

FANTOM5 (CAGE): breadth broad, TPM avg 6.1498 / max 440.8894, expressed in 612 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73804	2.2641	353
73811	1.1270	444
73803	1.0341	214
73800	0.6183	94
73802	0.3169	63
73801	0.1818	38
73807	0.1449	6
73810	0.1311	71
73806	0.1200	7
73795	0.0872	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal glomerulus	UBERON:0000074	99.73	gold quality
metanephric glomerulus	UBERON:0004736	99.69	gold quality
synovial joint	UBERON:0002217	99.04	gold quality
gluteal muscle	UBERON:0002000	99.03	gold quality
heart right ventricle	UBERON:0002080	99.00	gold quality
biceps brachii	UBERON:0001507	98.88	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.83	gold quality
germinal epithelium of ovary	UBERON:0001304	98.77	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.48	gold quality
triceps brachii	UBERON:0001509	97.83	gold quality
vastus lateralis	UBERON:0001379	97.79	gold quality
diaphragm	UBERON:0001103	97.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.33	gold quality
body of tongue	UBERON:0011876	97.20	gold quality
cardiac ventricle	UBERON:0002082	96.69	gold quality
parietal pleura	UBERON:0002400	96.63	gold quality
heart left ventricle	UBERON:0002084	96.62	gold quality
jejunal mucosa	UBERON:0000399	96.47	gold quality
gastrocnemius	UBERON:0001388	96.46	gold quality
lower lobe of lung	UBERON:0008949	96.26	gold quality
quadriceps femoris	UBERON:0001377	95.99	gold quality
muscle organ	UBERON:0001630	95.84	gold quality
skeletal muscle organ	UBERON:0014892	95.84	gold quality
skeletal muscle tissue	UBERON:0001134	95.79	gold quality
muscle of leg	UBERON:0001383	95.66	gold quality
apex of heart	UBERON:0002098	95.63	gold quality
colonic mucosa	UBERON:0000317	95.54	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.50	gold quality
jejunum	UBERON:0002115	95.27	gold quality
pleura	UBERON:0000977	95.05	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	2610.11
E-CURD-119	yes	2572.20
E-GEOD-114530	yes	1820.27
E-HCAD-10	yes	887.27
E-GEOD-130148	yes	7.91
E-ENAD-17	no	69.80
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

232 targeting CLIC5, 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-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4493	99.90	66.48	977

Literature-anchored findings (GeneRIF, showing 11)

• association with Golgi apparatus AKAP350 (PMID:12163479)
• CLIC-5A has a role as a chloride channel in vitro and binds to cortical actin cytoskeleton (PMID:15184393)
• CLIC5 was demonstrated in cultured lymphoblasts. (PMID:17492382)
• Data showed that CLIC1 and CLIC5, but not CLIC4, were strongly and reversibly inhibited (or inactivated) by F-actin. (PMID:18028448)
• CLIC5A colocalizes with ezrin and podocalyxin in podocytes and is required for the development/maintenance of the proper glomerular endothelial cell and podocyte architecture. (PMID:20335315)
• CLIC5 is a novel gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction. (PMID:24781754)
• The mechanism of CLIC5A action involves clustered plasma membrane phosphatidylinositol 4,5-bisphosphate accumulation, in turn facilitating ezrin activation and actin-dependent cell surface remodeling. (PMID:25344252)
• EZR, CLIC5 and PODXL are overexpressed in hepatocellular carcinoma and may have a role in cell migration and invasiveness (PMID:26135398)
• loss of ETV6 leads to significant overexpression of CLIC5, which in turn leads to decreased lysosome-mediated apoptosis. Our data suggest that heightened CLIC5 activity could promote a permissive environment for oxidative stress-induced DNA damage accumulation, and thereby contribute to leukemogenesis. (PMID:27540136)
• Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment. (PMID:33114113)
• A comprehensively prognostic and immunological analysis of chloride intracellular channel protein 5 (CLIC5) in pan-cancer and identification in ovarian cancer. (PMID:37286734)

Cross-species orthologs

35 orthologs

Organism	Symbol	Gene ID
danio_rerio	clic5b	ENSDARG00000070584
danio_rerio	clic5a	ENSDARG00000075993
mus_musculus	Clic5	ENSMUSG00000023959
rattus_norvegicus	Clic5	ENSRNOG00000074354
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), GDAP1L1 (ENSG00000124194), GSTT2B (ENSG00000133433), GSTO1 (ENSG00000148834), CLIC2 (ENSG00000155962), CLIC6 (ENSG00000159212), CLIC4 (ENSG00000169504), CLIC3 (ENSG00000169583), CLIC1 (ENSG00000213719), EEF1G (ENSG00000254772), GSTT4 (ENSG00000276950)

Protein

Protein identifiers

Chloride intracellular channel protein 5 — Q9NZA1 (reviewed: Q9NZA1)

Alternative names: Glutaredoxin-like oxidoreductase CLIC5

All UniProt accessions (6): A0A2R8Y4M1, A0A2R8Y615, A0A2R8YGW2, A0A5F9ZHK1, Q9NZA1, Q53G01

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 non-selective ion channels almost equally permeable to Na(+), K(+) and Cl(-). Required for normal hearing. It is necessary for the formation of stereocilia in the inner ear and normal development of the organ of Corti. May play a role in the regulation of transepithelial ion absorption and secretion. Is required for the development and/or maintenance of the proper glomerular endothelial cell and podocyte architecture. Plays a role in formation of the lens suture in the eye, which is important for normal optical properties of the lens.

Subunit / interactions. Component of a multimeric complex consisting of several cytoskeletal proteins, including actin, ezrin, alpha-actinin, gelsolin, and IQGAP1. Interacts with AKAP9. Interacts with TPRN. TPRN, CLIC5 and PTPQR form concentric rings at the base of stereocilia and may form a complex. Interacts with EZR, MYO6 and RDX; the proteins may work together as a complex to stabilize linkages between the plasma membrane and subjacent actin cytoskeleton at the stereocilium base.

Subcellular location. Cytoplasm. Cytoskeleton. Cell cortex. Membrane. Apical cell membrane. Mitochondrion. Cell projection. Stereocilium Golgi apparatus. Microtubule organizing center. Centrosome.

Tissue specificity. Widely expressed in both fetal and adult human tissues. Isoform 1 is expressed in renal glomeruli endothelial cells and podocytes (at protein level).

Disease relevance. Deafness, autosomal recessive, 103 (DFNB103) [MIM:616042] A form of sensorineural deafness with onset in early childhood. Hearing impairment progresses from mild to severe or even profound before the second decade, and is accompanied by vestibular areflexia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by F-actin.

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 (3)

UniProt ID	Names	Canonical?
Q9NZA1-1	2, CLIC5B	yes
Q9NZA1-2	1, CLIC5A
Q9NZA1-3	3

RefSeq proteins (5): NP_001107558, NP_001242952, NP_001357578, NP_001357579, NP_058625* (*=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
IPR042069	CLIC5_C_GST	Domain
IPR053823	CLIC_N	Domain

Pfam: PF13410, PF22441

Catalyzed reactions (Rhea), 3 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• chloride(in) = chloride(out) (RHEA:29823)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (33 total): helix 11, strand 6, splice variant 5, turn 3, sequence variant 2, sequence conflict 2, chain 1, transmembrane region 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8Q4I	X-RAY DIFFRACTION	2.1
6Y2H	X-RAY DIFFRACTION	2.15
8Q4J	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZA1-F1	68.06	0.47

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 203 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, LFA1_Q6, GOBP_INORGANIC_ANION_TRANSPORT, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_CHLORIDE_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOCC_CENTROSOME, GOBP_MULTI_MULTICELLULAR_ORGANISM_PROCESS, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_SENSORY_PERCEPTION, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, GOCC_NEURON_PROJECTION, CUI_TCF21_TARGETS_2_DN, BOQUEST_STEM_CELL_DN

GO Biological Process (7): chloride transport (GO:0006821), female pregnancy (GO:0007565), visual perception (GO:0007601), sensory perception of sound (GO:0007605), 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 (15): mitochondrion (GO:0005739), Golgi apparatus (GO:0005794), centrosome (GO:0005813), cell cortex (GO:0005938), actin cytoskeleton (GO:0015629), apical plasma membrane (GO:0016324), stereocilium (GO:0032420), chloride channel complex (GO:0034707), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
intracellular membrane-bounded organelle	2
cell periphery	2
monoatomic anion transport	1
inorganic anion transport	1
multi-organism reproductive process	1
multi-multicellular organism process	1
sensory perception of light stimulus	1
sensory perception of mechanical stimulus	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
endomembrane system	1
centriole	1
microtubule organizing center	1
cytoskeleton	1
apical part of cell	1
plasma membrane region	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
monoatomic ion channel complex	1
extracellular vesicle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
membrane	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLIC5	TPRN	Q4KMQ1	919
CLIC5	EZR	P15311	798
CLIC5	RDX	P35241	773
CLIC5	GRXCR2	A6NFK2	671
CLIC5	TMC1	Q8TDI8	522
CLIC5	MYO6	Q9UM54	478
CLIC5	CDH23	Q9H251	463
CLIC5	ADGRV1	Q8WXG9	460
CLIC5	PCDH15	Q96QU1	455
CLIC5	AADACL2	Q6P093	451
CLIC5	USH2A	O75445	445
CLIC5	KCNQ4	P56696	438
CLIC5	SLC26A5	P58743	436
CLIC5	MYO7A	P78427	410
CLIC5	PTPRQ	Q9UMZ3	400

IntAct

11 interactions, top by confidence:

A	B	Type	Score
CLIC4	CLIC2	psi-mi:“MI:0914”(association)	0.530
CLIC5	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CLIC5	SRPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CLIC5	SRC	psi-mi:“MI:0915”(physical association)	0.400
SRC	CLIC5	psi-mi:“MI:0915”(physical association)	0.400
CLIC5	CLIC2	psi-mi:“MI:0914”(association)	0.350
CLIC5	NME6	psi-mi:“MI:0914”(association)	0.350
FN1	ESYT2	psi-mi:“MI:0914”(association)	0.350
Fyn	CLIC5	psi-mi:“MI:0914”(association)	0.350
CLIC5	LAMTOR5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): CLIC5 (Affinity Capture-MS), CLIC2 (Affinity Capture-MS), TPRN (Affinity Capture-MS), CLIC5 (Co-fractionation), TPRN (Affinity Capture-MS), CLIC2 (Affinity Capture-MS), CLIC5 (Affinity Capture-MS), TPRN (Two-hybrid), CLIC5 (Two-hybrid), CLIC5 (Reconstituted Complex), PLS1 (Affinity Capture-MS), CLIC5 (Affinity Capture-MS), TPRN (Affinity Capture-MS), CLIC2 (Affinity Capture-MS), MAPK3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JZ79, A7E379, A8PJJ2, B0W041, B0WGN4, B0WV73, B0XHW8, B3MN22, B3P6R5, B3RYZ0, B4GX14, B4HXA6, B4IJG7, B4JCX8, B4KEN8, B4M8L8, B4MVR2, B4P3Q9, B4Q572, B5DFW7, B5DK05, B7PZ18, B9WCK0, C4R0B5, C4Y3K5, C5DHL6, C5DU06, C5M7P6, D3ZY68, E1FU46, E3MIE2, E3WSB5, O74550, P53260, Q09705, Q16Q94, Q2M1D1, Q5FWF4, Q6C5P0, Q6CDJ8

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, A2XMN2, A6QQZ0, A8XT16, F4IA73, O09131, O43708, O88741, P0ACA3, P0ACA4, P0ACA5, P0ACA6, P28342, P30347, P31784

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FYN	“up-regulates activity”	CLIC5	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	91
Likely benign	58
Benign	29

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1075907	NC_000006.11:g.(?45296464)(46047979_?)del	Pathogenic
160365	NM_016929.5(CLIC5):c.96T>A (p.Cys32Ter)	Pathogenic
3246086	NC_000006.11:g.(?45479963)(45923001_?)del	Pathogenic
3601021	NM_016929.5(CLIC5):c.535del (p.Asp179fs)	Pathogenic
1341311	GRCh37/hg19 6p21.1(chr6:45284656-46157024)x3	Likely pathogenic
694310	NM_016929.5(CLIC5):c.644G>A (p.Trp215Ter)	Likely pathogenic

SpliceAI

1387 predictions. Top by Δscore:

Variant	Effect	Δscore
6:45903252:CAAT:C	acceptor_gain	1.0000
6:45903255:TC:T	acceptor_loss	1.0000
6:45941540:CACT:C	donor_loss	1.0000
6:45941541:ACTC:A	donor_loss	1.0000
6:45941542:CTCA:C	donor_loss	1.0000
6:45941543:T:TA	donor_loss	1.0000
6:45941544:CAC:C	donor_loss	1.0000
6:45941545:A:AC	donor_gain	1.0000
6:45941545:A:AT	donor_loss	1.0000
6:45941546:C:CC	donor_gain	1.0000
6:45941546:C:G	donor_loss	1.0000
6:45941546:CCAG:C	donor_gain	1.0000
6:45949250:CCTTA:C	donor_loss	1.0000
6:45949251:CTTA:C	donor_loss	1.0000
6:45949252:TTACT:T	donor_loss	1.0000
6:45949253:TA:T	donor_loss	1.0000
6:45949254:A:AC	donor_gain	1.0000
6:45949254:ACT:A	donor_loss	1.0000
6:45949255:C:CA	donor_gain	1.0000
6:45949255:C:G	donor_loss	1.0000
6:45949255:CT:C	donor_gain	1.0000
6:45949255:CTT:C	donor_gain	1.0000
6:45949255:CTTT:C	donor_gain	1.0000
6:45949255:CTTTT:C	donor_gain	1.0000
6:45949378:CTTT:C	acceptor_gain	1.0000
6:45949379:TTT:T	acceptor_gain	1.0000
6:45949379:TTTC:T	acceptor_loss	1.0000
6:45949380:TT:T	acceptor_gain	1.0000
6:45949382:C:CC	acceptor_gain	1.0000
6:45949382:CTGTA:C	acceptor_loss	1.0000

AlphaMissense

1654 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:45941596:A:C	F278L	1.000
6:45941596:A:T	F278L	1.000
6:45941598:A:G	F278L	1.000
6:45955214:A:G	C191R	1.000
6:45914241:A:G	L351P	0.999
6:45914253:A:G	L347P	0.999
6:45914258:G:C	C345W	0.999
6:45914260:A:G	C345R	0.999
6:45941572:T:A	K286N	0.999
6:45941572:T:G	K286N	0.999
6:45941573:T:A	K286I	0.999
6:45941574:T:C	K286E	0.999
6:45949331:A:G	L234P	0.999
6:45949337:G:T	P232H	0.999
6:45949340:G:T	P231Q	0.999
6:45949355:G:T	A226D	0.999
6:45955161:G:C	F208L	0.999
6:45955161:G:T	F208L	0.999
6:45955163:A:G	F208L	0.999
6:45955177:A:G	L203P	0.999
6:45955191:G:C	F198L	0.999
6:45955191:G:T	F198L	0.999
6:45955193:A:G	F198L	0.999
6:45955198:C:G	R196P	0.999
6:45955206:G:C	F193L	0.999
6:45955206:G:T	F193L	0.999
6:45955208:A:G	F193L	0.999
6:45955212:A:C	C191W	0.999
6:45955219:C:T	G189D	0.999
6:45903163:G:C	F386L	0.998

dbSNP variants (sampled 300 via entrez): RS1000011800 (6:46062135 G>A), RS1000036528 (6:46104749 G>A), RS1000040608 (6:45953686 T>C), RS1000049165 (6:46103530 A>C,T), RS1000069153 (6:46109869 T>C), RS1000072028 (6:46030142 G>A), RS1000076822 (6:45924216 A>T), RS1000083574 (6:46061854 A>C), RS1000083874 (6:45946845 G>A,C), RS1000137216 (6:46076864 G>A), RS1000162099 (6:46109563 G>A,T), RS1000163851 (6:45969601 C>A,T), RS1000183051 (6:45997360 G>A,T), RS1000202541 (6:46123822 C>G), RS1000205882 (6:46127152 A>C)

Disease associations

OMIM: gene MIM:607293 | disease phenotypes: MIM:616042, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Supportive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 103	Limited	Autosomal recessive

Mondo (3): hearing loss disorder (MONDO:0005365), autosomal recessive nonsyndromic hearing loss 103 (MONDO:0014469), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (2): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C564609	Deafness, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	4
sodium arsenite	increases expression, decreases expression	2
Diethylhexyl Phthalate	increases abundance, increases methylation, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Estradiol	affects expression	1
Hydrogen Peroxide	affects expression	1
Nickel	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tretinoin	increases expression	1
Triclosan	decreases expression	1
Sodium Selenite	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YA42	IDG-HEK293T-CLIC5-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss