CLDN14

Summary

CLDN14 (claudin 14, HGNC:2035) is a protein-coding gene on chromosome 21q22.13, encoding Claudin-14 (O95500). Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.

Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. The encoded protein also binds specifically to the WW domain of Yes-associated protein. Defects in this gene are the cause of an autosomal recessive form of nonsyndromic sensorineural deafness. It is also reported that four synonymous variants in this gene are associated with kidney stones and reduced bone mineral density. Several transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 23562 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 160 total — 10 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 4
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001146079

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2035
Approved symbol	CLDN14
Name	claudin 14
Location	21q22.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000159261
Ensembl biotype	protein_coding
OMIM	605608
Entrez	23562

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000342108, ENST00000399135, ENST00000399136, ENST00000399137, ENST00000399139, ENST00000877609, ENST00000877610, ENST00000877611, ENST00000877612, ENST00000877613, ENST00000877614, ENST00000877615, ENST00000877616, ENST00000877617, ENST00000877618, ENST00000877619

RefSeq mRNA: 5 — MANE Select: NM_001146079 NM_001146077, NM_001146078, NM_001146079, NM_012130, NM_144492

CCDS: CCDS13645

Canonical transcript exons

ENST00000399135 — 2 exons

Exon	Start	End
ENSE00001369937	36460621	36461776
ENSE00003845730	36479495	36480122

Expression profiles

Bgee: expression breadth broad, 84 present calls, max score 89.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4672 / max 46.4854, expressed in 138 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190364	0.3310	108
190365	0.0543	11
190370	0.0499	17
190366	0.0130	6
190371	0.0084	3
190369	0.0069	4
190368	0.0038	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	89.44	gold quality
liver	UBERON:0002107	82.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.32	gold quality
endometrium epithelium	UBERON:0004811	70.94	gold quality
metanephros cortex	UBERON:0010533	69.47	gold quality
buccal mucosa cell	CL:0002336	69.13	silver quality
adult mammalian kidney	UBERON:0000082	66.15	gold quality
metanephros	UBERON:0000081	63.65	gold quality
kidney	UBERON:0002113	63.62	gold quality
pancreatic ductal cell	CL:0002079	63.21	silver quality
heart right ventricle	UBERON:0002080	60.43	gold quality
triceps brachii	UBERON:0001509	60.21	gold quality
Brodmann (1909) area 10	UBERON:0013541	59.90	gold quality
cortex of kidney	UBERON:0001225	59.73	gold quality
gluteal muscle	UBERON:0002000	59.10	gold quality
secondary oocyte	CL:0000655	59.09	gold quality
nephron tubule	UBERON:0001231	59.07	silver quality
skin of hip	UBERON:0001554	58.54	silver quality
cartilage tissue	UBERON:0002418	58.49	silver quality
decidua	UBERON:0002450	58.40	gold quality
parotid gland	UBERON:0001831	57.74	gold quality
kidney epithelium	UBERON:0004819	56.32	silver quality
body of pancreas	UBERON:0001150	55.09	gold quality
deltoid	UBERON:0001476	53.66	gold quality
nasal cavity epithelium	UBERON:0005384	53.24	gold quality
vena cava	UBERON:0004087	53.01	gold quality
skeletal muscle tissue	UBERON:0001134	53.00	gold quality
pancreas	UBERON:0001264	52.92	gold quality
renal medulla	UBERON:0000362	52.87	gold quality
hair follicle	UBERON:0002073	52.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting CLDN14, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5193	100.00	67.26	1744
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-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-146B-3P	97.83	65.29	782
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-339-5P	96.73	66.01	820
HSA-MIR-1238-3P	95.27	62.25	552

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 24)

• The palmitoylation of claudin-14 is required for efficient localization into tight junctions but not stability or strand assembly. (PMID:15769849)
• The ability of CLDN14 to be recruited to these junctions is crucial for the hearing process. (PMID:15880785)
• Common, synonymous variants in the CLDN14 gene that associate with kidney stones, were discovered. (PMID:19561606)
• The CLDN14 promoter is activated by Trichostatin A (TSA) treatment according to promoter reporter assays in HEK 293 cells. (PMID:20494980)
• Individuals with mutations of CLDN14 may have different degrees of hearing loss and the loss is greater at higher frequencies. (PMID:20811388)
• The hearing loss due to novel CLDN14 mutations is prelingual, severe-to-profound with greater loss in the high frequencies. (PMID:22246673)
• OPRM1 genetic polymorphisms are associated with the plasma concentration of cotinine in a Taiwanese MMT cohort. Carriers with the major allele of SNP rs1799971 had a higher plasma cotinine concentration. (PMID:23235333)
• Human Cldn-8 and -14 were shown to convey Clostridium perfringens enterotoxin-mediated cytotoxicity at pathophysiologically relevant concentrations of this toxin, although ~2-to-10-fold less efficiently than Cldn-4. (PMID:23322640)
• CLDN14 mutations can contribute to the aetiology of childhood/congenital deafness in Moroccan patients. (PMID:23590985)
• Data suggest a possible role for Claudin14 in urinary calcium excretion. (PMID:23991001)
• Claudin 14 expression was up-regulated in gastric cancer. (PMID:24325792)
• Rs1801725 (Ala986-Ser), rs1042636 (Arg990Gly) of CaSR gene and rs219778, rs219780 (Thr229Thr) of CLDN14 gene were significantly associated with kidney stone disease in patients from the Eastern part of India. (PMID:26107257)
• The rs170183 was correlated with a decline in claudin 14 expression in both lymphoblastoid cell lines and T cells. (PMID:26842849)
• CLDN14 is a novel direct target of EZH2-mediated H3K27ME3 and plays role in EZH2-H3K27ME3-mediated hepatocellular carcinoma aggressiveness. (PMID:27207647)
• All hearing impaired individuals, including the proband, are homozygous for a pathogenic variant of CLDN14, but this only explains the deafness. (PMID:27629923)
• Extensive clinical recruitment and targeted screening suggest that CLDN14 p.(Ala163Val) represents a major founder variant for prelingual sensorineural hearing loss in the Newfoundland population. (PMID:27838790)
• Our data suggest that children with the INSM1 binding site within the CLDN14 risk haplotype have a higher likelihood of hypercalciuria and kidney stones. Enhanced CLDN14 expression may play a role in the pathophysiology of their hypercalciuria. (PMID:28229505)
• This study suggested considerable genetic heterogeneity in the causation of hearing loss in Dhadkai. Recessive mutations were observed in at least three genes causing hearing loss: OTOF (p.R708X), SLC26A4 (p.Y556X) and CLDN14 (p.V85D). Mutation p.R708X appeared to be the major cause of hearing impairment in Dhadkai. (PMID:29434063)
• CLDN14 might not be a major causative gene for NSHL in Chinese populations, which would contribute to fully understanding the genetic cause of NSHL in the East Asian populations (PMID:29447821)
• No significant associations were found among claudin-16 and claudin-19 single-nucleotide polymorphisms and calcium excretion and between claudin-14, claudin-16, and claudin-19 single-nucleotide polymorphisms and stones (PMID:30232134)
• This report indicated that claudin-14 is essential for maintaining the inner ear environment and suggested the possible phenotypic expansion of DFNB29. This is the first report of a patient with a tight junction variant receiving a cochlear implantation. (PMID:31527509)
• The correlation between promoter hypermethylation of VDR, CLDN, and CasR genes and recurrent stone formation. (PMID:35546405)
• Downregulation of chemoresistance by claudin-14 silencing in human colorectal cancer cells. (PMID:38942107)
• Diabetes compromises tight junction protein claudin 14 in the urinary bladder. (PMID:39162877)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cldn14	ENSMUSG00000047109
rattus_norvegicus	Cldn14	ENSRNOG00000001691

Paralogs (22): CLDN11 (ENSG00000013297), CLDN18 (ENSG00000066405), CLDN15 (ENSG00000106404), CLDN16 (ENSG00000113946), CLDN10 (ENSG00000134873), CLDN17 (ENSG00000156282), CLDN8 (ENSG00000156284), CLDN1 (ENSG00000163347), CLDN19 (ENSG00000164007), CLDN3 (ENSG00000165215), CLDN2 (ENSG00000165376), CLDN20 (ENSG00000171217), CLDN22 (ENSG00000177300), CLDN7 (ENSG00000181885), CLDN5 (ENSG00000184113), CLDN6 (ENSG00000184697), CLDN24 (ENSG00000185758), CLDN4 (ENSG00000189143), CLDN9 (ENSG00000213937), CLDN25 (ENSG00000228607), CLDN34 (ENSG00000234469), CLDN23 (ENSG00000253958)

Protein

Protein identifiers

Claudin-14 — O95500 (reviewed: O95500)

All UniProt accessions (1): O95500

UniProt curated annotations — full annotation on UniProt →

Function. Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.

Subcellular location. Cell junction. Tight junction. Cell membrane.

Tissue specificity. Liver, kidney. Also found in ear.

Disease relevance. Deafness, autosomal recessive, 29 (DFNB29) [MIM:614035] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the claudin family.

RefSeq proteins (5): NP_001139549, NP_001139550, NP_001139551, NP_036262, NP_652763 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR006187	Claudin	Family
IPR017974	Claudin_CS	Conserved_site

Pfam: PF00822

UniProt features (19 total): sequence variant 7, topological domain 5, transmembrane region 4, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95500-F1	80.00	0.47

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-420029	Tight junction interactions

MSigDB gene sets: 113 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, RNGTGGGC_UNKNOWN, CCAWYNNGAAR_UNKNOWN, KEGG_TIGHT_JUNCTION, MEF2_02, GOBP_CELL_CELL_ADHESION, MODULE_379, GATA1_04, MODULE_242, GOCC_CELL_CELL_JUNCTION, MODULE_207, chr21q22, MEF2_Q6_01, MODULE_95, HOXA4_Q2

GO Biological Process (4): cell adhesion (GO:0007155), calcium-independent cell-cell adhesion (GO:0016338), protein-containing complex assembly (GO:0065003), bicellular tight junction assembly (GO:0070830)

GO Molecular Function (3): structural molecule activity (GO:0005198), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cell-cell junction organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
cell-cell adhesion	1
cellular component assembly	1
protein-containing complex organization	1
apical junction assembly	1
tight junction assembly	1
molecular_function	1
protein binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

644 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLDN14	TJP2	Q9UDY2	723
CLDN14	TJP1	Q07157	700
CLDN14	CASR	P41180	666
CLDN14	CLDN12	P56749	622
CLDN14	OCLN	Q16625	593
CLDN14	TMPRSS3	P57727	588
CLDN14	MARVELD2	Q8N4S9	585
CLDN14	ILDR1	Q86SU0	580
CLDN14	GJB2	P29033	530
CLDN14	OTOG	Q6ZRI0	506
CLDN14	TMIE	Q8NEW7	506
CLDN14	SLC26A4	O43511	504
CLDN14	STRC	Q7RTU9	499
CLDN14	TMC1	Q8TDI8	499
CLDN14	TRPV5	Q9NQA5	491

IntAct

124 interactions, top by confidence:

A	B	Type	Score
CLDN14	PLLP	psi-mi:“MI:0915”(physical association)	0.560
CLDN14	CTXN3	psi-mi:“MI:0915”(physical association)	0.560
CLDN14	MAL	psi-mi:“MI:0915”(physical association)	0.560
CLDN14	PLEKHA1	psi-mi:“MI:0915”(physical association)	0.490
CLDN14	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
HTRA3	CLDN14	psi-mi:“MI:0407”(direct interaction)	0.440
HTRA1	CLDN14	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	TJP3	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	NOS1	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
PICK1	CLDN14	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI2	CLDN14	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	LIN7B	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	IL16	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN14	RAPGEF6	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (4): PLEKHA1 (Two-hybrid), CLDN14 (Two-hybrid), MAL (Two-hybrid), CTXN3 (Two-hybrid)

ESM2 similar proteins: A6NFC5, A6NM45, A8MUP6, B1AQL3, C3VMW3, C9JDP6, O35912, O75204, O88551, O88552, O95500, O95832, P56745, P56746, P56748, P56750, P57739, Q08DE1, Q0V9E0, Q0VCN0, Q16617, Q2KIY2, Q2KJ11, Q3UUA0, Q4V922, Q5CZV0, Q5M962, Q5QT56, Q6ICI0, Q765P1, Q7T392, Q7TQI0, Q7Z7N9, Q8BGP5, Q8BXA6, Q8N7P3, Q8NHS1, Q8VHW3, Q95KM6, Q96B33

Diamond homologs: A0A8C0N7E5, A6NM45, C3VMW3, C9JDP6, D3ZQJ0, O00501, O14493, O15551, O19005, O35054, O54942, O75508, O88551, O88552, O95471, O95484, O95500, O95832, P56745, P56746, P56747, P56748, P56750, P56856, P56857, P56880, P57739, P78369, Q0VCN0, Q2HJ22, Q2KIY2, Q3B7N4, Q3MHK4, Q4R3L1, Q5E9L0, Q5I0E5, Q5QT56, Q5R8E5, Q60771, Q63400

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	57.1×	9e-07
Unblocking of NMDA receptors, glutamate binding and activation	5	54.4×	9e-07
Negative regulation of NMDA receptor-mediated neuronal transmission	5	54.4×	9e-07
Assembly and cell surface presentation of NMDA receptors	10	50.8×	3e-13
Dopamine Neurotransmitter Release Cycle	5	49.6×	1e-06
Long-term potentiation	5	47.6×	1e-06
Neurexins and neuroligins	11	43.3×	1e-13
Protein-protein interactions at synapses	7	37.2×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	81.8×	9e-15
protein localization to synapse	6	64.7×	5e-08
receptor clustering	7	61.5×	4e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	41.9×	5e-07
cell-cell adhesion	10	14.3×	2e-07
protein-containing complex assembly	7	11.2×	1e-04
protein localization to plasma membrane	5	7.7×	8e-03
chemical synaptic transmission	7	7.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	91
Likely benign	28
Benign	6

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
189332	NM_001146079.2(CLDN14):c.167G>A (p.Trp56Ter)	Pathogenic
2074442	NM_001146079.2(CLDN14):c.548_588dup (p.Pro197fs)	Pathogenic
2749812	NM_001146079.2(CLDN14):c.203del (p.Arg68fs)	Pathogenic
3601010	NM_001146079.2(CLDN14):c.554_556del (p.Cys185_Gln186delinsTer)	Pathogenic
3601931	NM_001146079.2(CLDN14):c.167_168del (p.Trp56fs)	Pathogenic
3601941	NM_001146079.2(CLDN14):c.285C>A (p.Cys95Ter)	Pathogenic
3601952	NM_001146079.2(CLDN14):c.355_361del (p.Ile119fs)	Pathogenic
4807142	NM_001146079.2(CLDN14):c.611del (p.Thr204fs)	Pathogenic
4845581	NM_001146079.2(CLDN14):c.202C>T (p.Arg68Ter)	Pathogenic
984395	NM_001146079.2(CLDN14):c.40_41insTGGTGCACGGCCGTGCA (p.Ser14fs)	Pathogenic
1810013	NM_001146079.2(CLDN14):c.414G>A (p.Trp138Ter)	Likely pathogenic
2972749	NM_001146079.2(CLDN14):c.242_243delinsAT (p.Arg81His)	Likely pathogenic
497748	NM_001146079.2(CLDN14):c.401del (p.Val134fs)	Likely pathogenic
599168	NM_001146079.2(CLDN14):c.191G>A (p.Cys64Tyr)	Likely pathogenic

SpliceAI

1073 predictions. Top by Δscore:

Variant	Effect	Δscore
21:36461772:GAGCC:G	acceptor_gain	0.9900
21:36461774:GCCCT:G	acceptor_loss	0.9900
21:36461775:CC:C	acceptor_gain	0.9900
21:36461776:CC:C	acceptor_gain	0.9900
21:36461776:CCTA:C	acceptor_loss	0.9900
21:36461777:C:CA	acceptor_loss	0.9900
21:36461777:C:CC	acceptor_gain	0.9900
21:36461778:T:A	acceptor_loss	0.9900
21:36461787:C:CT	acceptor_gain	0.9900
21:36461788:A:T	acceptor_gain	0.9900
21:36461802:C:CT	acceptor_gain	0.9900
21:36461773:AGCC:A	acceptor_gain	0.9800
21:36461777:C:T	acceptor_gain	0.9800
21:36461787:C:T	acceptor_gain	0.9800
21:36461796:C:CT	acceptor_gain	0.9800
21:36461797:G:T	acceptor_gain	0.9800
21:36541083:T:TA	donor_gain	0.9800
21:36542563:ACC:A	donor_gain	0.9800
21:36542564:CCC:C	donor_gain	0.9800
21:36461774:GCC:G	acceptor_gain	0.9700
21:36461775:CCC:C	acceptor_gain	0.9700
21:36461803:A:T	acceptor_gain	0.9700
21:36461780:A:AC	acceptor_gain	0.9600
21:36461780:A:C	acceptor_gain	0.9600
21:36508321:T:A	donor_gain	0.9600
21:36469870:TTAAA:T	donor_gain	0.9500
21:36469871:TAAAT:T	donor_gain	0.9500
21:36469872:AAATA:A	donor_gain	0.9500
21:36516440:T:TA	donor_gain	0.9500
21:36516441:C:A	donor_gain	0.9500

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000012288 (21:36507906 A>G), RS1000047371 (21:36571717 C>A,G), RS1000052467 (21:36470475 C>G), RS1000072848 (21:36542794 G>A,T), RS1000113206 (21:36464345 G>A,C), RS1000141041 (21:36553155 G>A,T), RS1000152957 (21:36514318 G>T), RS1000171298 (21:36491241 A>T), RS1000217777 (21:36542522 C>A,G,T), RS1000228225 (21:36570069 T>G), RS1000269531 (21:36570484 G>A), RS1000288307 (21:36496525 C>G,T), RS1000292260 (21:36502749 G>C), RS1000350048 (21:36508976 C>T), RS1000351953 (21:36497555 T>C)

Disease associations

OMIM: gene MIM:605608 | disease phenotypes: MIM:301050, MIM:614035, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 29	Definitive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (7): hearing loss disorder (MONDO:0005365), Alport syndrome (MONDO:0018965), autosomal recessive nonsyndromic hearing loss 29 (MONDO:0013537), vein of Galen aneurysm (MONDO:0015196), hearing loss, autosomal recessive (MONDO:0019588), sensorineural hearing loss disorder (MONDO:0020678), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (4): Alport syndrome (Orphanet:63), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Vein of Galen malformation (Orphanet:1053), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0003680	Nonprogressive

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST000429_1	Kidney stones	4.000000e-12
GCST002276_18	Bone mineral density	4.000000e-09
GCST002276_19	Bone mineral density	6.000000e-08
GCST002276_24	Bone mineral density	2.000000e-07
GCST003086_3	Kidney stones	5.000000e-13
GCST003879_6	Serum parathyroid hormone levels	9.000000e-22
GCST003929_1	Urinary electrolytes (magnesium/calcium ratio)	2.000000e-12
GCST004604_1	Hematocrit	2.000000e-16
GCST004615_133	Hemoglobin concentration	1.000000e-13
GCST005984_69	Glomerular filtration rate	9.000000e-10
GCST006979_181	Heel bone mineral density	2.000000e-20
GCST007833_17	Urolithiasis	6.000000e-13
GCST007876_128	Estimated glomerular filtration rate	5.000000e-08
GCST008058_217	Estimated glomerular filtration rate	2.000000e-12
GCST008059_190	Estimated glomerular filtration rate	7.000000e-12
GCST008062_83	Blood urea nitrogen levels	1.000000e-12
GCST008971_10	Urate levels	2.000000e-08
GCST008972_193	Urate levels	2.000000e-10
GCST009598_19	Kidney stones	7.000000e-21
GCST009599_13	Kidney stones	6.000000e-19
GCST010083_10	Hemoglobin levels	4.000000e-28
GCST012194_13	Obsessive-compulsive traits	2.000000e-06
GCST012490_172	Femur bone mineral density x serum urate levels interaction	3.000000e-08
GCST90002383_319	Hematocrit	1.000000e-40
GCST90002384_488	Hemoglobin	5.000000e-35
GCST90002403_541	Red blood cell count	6.000000e-28

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007903	magnesium:calcium ratio
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0009270	heel bone mineral density
EFO:0004531	urate measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (4)

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.)
C580334	Nonsyndromic Deafness (supp.)
C536535	Vein of Galen aneurysm (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	6
Aflatoxin B1	affects expression, decreases expression, increases methylation	5
lasiocarpine	decreases expression	2
methyleugenol	decreases expression	2
sodium arsenite	increases methylation, decreases expression	2
Acetaminophen	increases expression, decreases expression	2
N-Nitrosopyrrolidine	decreases expression	2
Cyclosporine	decreases expression, increases methylation	2
pirinixic acid	affects binding, decreases expression, increases activity	1
tributyltin	decreases expression	1
arsenite	affects binding, increases reaction	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
cobaltous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
methylmercury II	decreases expression	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
dimethylarsinous acid	increases expression	1
clothianidin	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	decreases expression	1
Ethanol	increases expression	1
Cannabinoids	affects methylation, increases abundance	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Quercetin	decreases expression	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

301 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
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
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