MARVELD2

Summary

MARVELD2 (MARVEL domain containing 2, HGNC:26401) is a protein-coding gene on chromosome 5q13.2, encoding MARVEL domain-containing protein 2 (Q8N4S9). Plays a role in the formation of tricellular tight junctions and of epithelial barriers.

The protein encoded by this gene is a membrane protein found at the tight junctions between epithelial cells. The encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49). Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 153562 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 257 total — 22 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 3
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001038603

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26401
Approved symbol	MARVELD2
Name	MARVEL domain containing 2
Location	5q13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ30532, TRIC
Ensembl gene	ENSG00000152939
Ensembl biotype	protein_coding
OMIM	610572
Entrez	153562

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 nonsense_mediated_decay

ENST00000325631, ENST00000413223, ENST00000436532, ENST00000454295, ENST00000512803, ENST00000515844, ENST00000645446, ENST00000647531, ENST00000882644, ENST00000882645, ENST00000882646, ENST00000882647, ENST00000882648

RefSeq mRNA: 2 — MANE Select: NM_001038603 NM_001038603, NM_001244734

CCDS: CCDS34175, CCDS58956

Canonical transcript exons

ENST00000325631 — 7 exons

Exon	Start	End
ENSE00001007955	69432527	69432675
ENSE00001007957	69424601	69424636
ENSE00001174822	69419371	69420531
ENSE00001287480	69440450	69440500
ENSE00001287489	69432922	69433093
ENSE00002074703	69441532	69444330
ENSE00003815572	69415116	69415170

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 90.11.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7940 / max 47.8695, expressed in 866 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56850	2.7252	844
56851	1.2750	416
56852	0.4958	274
56853	0.2981	207

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	90.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.15	gold quality
duodenum	UBERON:0002114	83.78	gold quality
pancreas	UBERON:0001264	83.05	gold quality
liver	UBERON:0002107	82.85	gold quality
rectum	UBERON:0001052	81.87	gold quality
mucosa of transverse colon	UBERON:0004991	81.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.70	gold quality
thyroid gland	UBERON:0002046	79.92	gold quality
left lobe of thyroid gland	UBERON:0001120	79.72	gold quality
right lobe of thyroid gland	UBERON:0001119	79.69	gold quality
right lobe of liver	UBERON:0001114	79.31	gold quality
body of pancreas	UBERON:0001150	79.28	gold quality
adult mammalian kidney	UBERON:0000082	78.15	gold quality
kidney	UBERON:0002113	77.88	gold quality
endometrium	UBERON:0001295	76.73	gold quality
esophagus mucosa	UBERON:0002469	75.91	gold quality
gall bladder	UBERON:0002110	75.37	gold quality
lung	UBERON:0002048	75.31	gold quality
placenta	UBERON:0001987	75.27	gold quality
tonsil	UBERON:0002372	74.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	73.74	gold quality
upper lobe of left lung	UBERON:0008952	72.96	gold quality
stomach	UBERON:0000945	72.79	gold quality
lower esophagus mucosa	UBERON:0035834	72.41	gold quality
saliva-secreting gland	UBERON:0001044	72.02	gold quality
right lung	UBERON:0002167	71.74	gold quality
minor salivary gland	UBERON:0001830	71.55	gold quality
body of stomach	UBERON:0001161	71.51	gold quality
colonic epithelium	UBERON:0000397	71.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.52

Regulation

Is transcription factor: no

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 31)

• Maps to 5q12.3-q14.1. (PMID:15538632)
• Splice-site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment (PMID:18084694)
• Data suggest that at low tricellulin expression the tricellular tight junction central tube forms a pathway, but at higher expression tricellulin forms a barrier for macromolecules in tricellular TJs and in bicellular TJs for solutes of all sizes. (PMID:19535456)
• Differential phosphorylation of tricellulin by casein kinase 1 (CK1) and casein kinase 2 (PMID:19538290)
• TRiC does not physically block the polyQ tract of Htt itself, but rather sequesters a short Htt sequence element, N-terminal to the polyQ tract, that promotes the amyloidogenic conformation. (PMID:19915590)
• These results suggest that tricellulin is stably expressed in human nasal epithelial cells and may play an important role for the sealing of the corner at tricellular contacts to prevent infiltration by various inhaled viruses and antigens. (PMID:20033365)
• marvelD3, occludin, and tricellulin define the tight junction-associated MARVEL protein family (PMID:20164257)
• JNK may be involved in the regulation of tricellular tight junctions including TRIC expression and the barrier function in pancreatic duct epithelial cells. (PMID:20533305)
• tricellulin is markedly reduced at all stages of tumor development. In situ hybridization analysis showed no correlation between HPV infection and altered expression of the tight junction proteins. (PMID:21480761)
• the expression of tricellulin both in microglia and in the stomach immune cells point to a possible role of this new tight junctions protein in the immune system. (PMID:21624353)
• tricellulin and its role in tight junction formation and maintenance (PMID:21868126)
• DFNB49 is an important cause of non-syndromic deafness in Czech Roma patients but not in the general Czech population. (PMID:22097895)
• the tricellulin expression profile in normal and neoplastic human pancreas (PMID:22394074)
• The dynamic behavior of tricellulin during the destruction and formation of tight junctions (TJ) under various extracellular calcium conditions seems to be closely associated with the barrier and fence functions of TJs. (PMID:23073616)
• The findings show the heterogeneity of the molecular organization of tTJs in terms of the content of LSR, ILDR1 or ILDR2, and suggest that ILDR1-mediated recruitment of tricellulin to TCs is required for hearing. (PMID:23239027)
• This study reveals the presence and subcellular distribution of tricellulin in brain endothelial cells. (PMID:23250572)
• High tricellulin expression is associated with hepatocellular carcinoma. (PMID:24652413)
• The expressions of MARVELD2, CLDN1 and CLDN3 mRNA were significantly lower in cholesteatoma tissue and may be involved in epithelium permeability. (PMID:25319490)
• MARVELD2 variants are responsible for about 1.5 % (95 % CI 0.8-2.6) of non-syndromic hearing loss in our cohort of 800 Pakistani families. The c.1331+2T>C allele is recurrent. (PMID:25666562)
• we demonstrated that PLG functions as a molecular bridge between tricellulin and streptococcal surface enolase (SEN). The wild type strain efficiently translocated across the epithelial monolayer, accompanied by cleavage of transmembrane junctional proteins. (PMID:26822058)
• GSK3beta may inhibit VRK2 catalytic activity by disrupting its flexibility. The inhibition of VRK2 catalytic activity by GSK3beta may also inhibit VRK2-induced degradation of TRiC, which could suppress polyQ-expanded Htt aggregation. (PMID:27377031)
• Our results provide new insights into the function of tricellulin, and its nuclear localization may become a new prognostic factor for pancreatic cancers. (PMID:27641742)
• Data show that the E3 ubiquitin ligase Itch forms a complex with tricellulin and thereby enhances its ubiquitination. (PMID:28436082)
• Tricellulin-dependent macromolecule passage was comparably regulated in leaky and tight epithelia, but relative and absolute ion permeabilities of the tricellular tight junction (tTJ) were different. (PMID:28605032)
• this study shows that tricellulin is regulated via interleukin-13-receptor alpha2, affects macromolecule uptake, and is decreased in ulcerative colitis (PMID:28612843)
• ELISA revealed that Crohn’s Disease twins demonstrated significantly lower levels of tight junction protein tricellulin compared with external controls. (PMID:29659773)
• Recessive insertion variant in the MARVELD2 segregates with non-syndromic hearing loss in an Iranian family. (PMID:29752989)
• Association of tricellulin expression with poor colorectal cancer prognosis and metastasis. (PMID:33000262)
• Co-occurrence of two rare genetic diseases: A potential pitfall for prenatal diagnosis in successive pregnancies. (PMID:33015857)
• Structural basis of plp2-mediated cytoskeletal protein folding by TRiC/CCT. (PMID:36921056)
• SARS-CoV-2 NSP12 associates with TRiC and the P323L substitution acts as a host adaption. (PMID:37929963)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	marveld2a	ENSDARG00000025076
danio_rerio	marveld2b	ENSDARG00000061651
mus_musculus	Marveld2	ENSMUSG00000021636
rattus_norvegicus	Marveld2	ENSRNOG00000018297
drosophila_melanogaster	Su(Tpl)	FBGN0014037
caenorhabditis_elegans		WBGENE00021281

Paralogs (5): OCEL1 (ENSG00000099330), ELL (ENSG00000105656), ELL2 (ENSG00000118985), ELL3 (ENSG00000128886), OCLN (ENSG00000197822)

Protein

Protein identifiers

MARVEL domain-containing protein 2 — Q8N4S9 (reviewed: Q8N4S9)

Alternative names: Tricellulin

All UniProt accessions (4): Q8N4S9, A1BQX2, D6RA09, D6RAH8

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the formation of tricellular tight junctions and of epithelial barriers. Required for normal hearing via its role in the separation of the endolymphatic and perilymphatic spaces of the organ of Corti in the inner ear, and for normal survival of hair cells in the organ of Corti.

Subunit / interactions. Interacts with TJP1. Interacts with the ubiquitin ligase ITCH. Interacts (via C-terminal cytoplasmic domain) with LSR (via the cytoplasmic domain), ILDR1 and ILDR2; the interaction is required to recruit MARVELD2 to tricellular contacts.

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

Post-translational modifications. Ubiquitinated by ITCH; but this ubiquitination does not lead to proteasomal degradation. Polyubiquitinated at Lys-412 via ‘Lys-63’-linked ubiquitin chains; deubiquitinated by USP53. Phosphorylated.

Disease relevance. Deafness, autosomal recessive, 49 (DFNB49) [MIM:610153] 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 ELL/occludin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N4S9-1	1, A, TRIC	yes
Q8N4S9-2	2, TRICbeta
Q8N4S9-3	3, A1

RefSeq proteins (2): NP_001033692, NP_001231663 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008253	Marvel	Domain
IPR010844	Occludin_ELL	Domain
IPR031176	ELL/occludin	Family

Pfam: PF01284, PF07303

UniProt features (39 total): topological domain 7, transmembrane region 6, helix 6, modified residue 5, splice variant 3, domain 2, region of interest 2, compositionally biased region 2, sequence conflict 2, chain 1, coiled-coil region 1, cross-link 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5N7H	X-RAY DIFFRACTION	2.2
5N7K	X-RAY DIFFRACTION	2.81
5N7I	X-RAY DIFFRACTION	2.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N4S9-F1	66.90	0.27

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 (6): 116, 120, 161, 166, 387, 412

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_APICAL_JUNCTION_ASSEMBLY, NKX62_Q2, GOBP_CELL_JUNCTION_ORGANIZATION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, GOBP_ENDOTHELIUM_DEVELOPMENT, GOCC_APICAL_PLASMA_MEMBRANE, AIGNER_ZEB1_TARGETS, GOBP_SENSORY_PERCEPTION, GOBP_CELL_JUNCTION_ASSEMBLY, GOBP_ESTABLISHMENT_OF_ENDOTHELIAL_BARRIER

GO Biological Process (4): sensory perception of sound (GO:0007605), cell-cell junction organization (GO:0045216), establishment of endothelial barrier (GO:0061028), bicellular tight junction assembly (GO:0070830)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): cytoplasm (GO:0005737), bicellular tight junction (GO:0005923), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), cell junction (GO:0030054), cytoplasmic vesicle (GO:0031410), paranodal junction (GO:0033010), Schmidt-Lanterman incisure (GO:0043220), tricellular tight junction (GO:0061689), tight junction (GO:0070160), plasma membrane (GO:0005886), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
tight junction	2
plasma membrane region	2
cell-cell junction	2
sensory perception of mechanical stimulus	1
cell junction organization	1
endothelial cell development	1
apical junction assembly	1
tight junction assembly	1
binding	1
intracellular anatomical structure	1
apical junction complex	1
basal plasma membrane	1
apical part of cell	1
cytoplasm	1
intracellular vesicle	1
compact myelin	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

797 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARVELD2	TJP1	Q07157	998
MARVELD2	TJP2	Q9UDY2	997
MARVELD2	TJP3	O95049	995
MARVELD2	OCLN	Q16625	989
MARVELD2	CGN	Q9P2M7	987
MARVELD2	CLDN7	O95471	960
MARVELD2	LSR	Q86X29	948
MARVELD2	F11R	Q9Y624	918
MARVELD2	J3KSM2	J3KSM2	916
MARVELD2	CLDN3	O15551	904
MARVELD2	ILDR2	Q71H61	893
MARVELD2	CLDN1	O95832	887
MARVELD2	ILDR1	Q86SU0	855
MARVELD2	AFDN	P55196	819
MARVELD2	CLDN2	P57739	793

IntAct

25 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MARVELD2	FATE1	psi-mi:“MI:0915”(physical association)	0.560
MARVELD2	PLG	psi-mi:“MI:0407”(direct interaction)	0.540
MARVELD2	PLG	psi-mi:“MI:0915”(physical association)	0.540
MARVELD2	GAP43	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
ABL1	MARVELD2	psi-mi:“MI:0407”(direct interaction)	0.440
MARVELD2	RAP2A	psi-mi:“MI:0914”(association)	0.350
MARVELD2	Ptpn6	psi-mi:“MI:0914”(association)	0.350
MFSD2B	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
SLC10A6	GNPAT	psi-mi:“MI:0914”(association)	0.350
SLC15A3	GXYLT2	psi-mi:“MI:0914”(association)	0.350
MCM7		psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TMEM216	SNAP23	psi-mi:“MI:2364”(proximity)	0.270
KRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
HRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CTDSPL	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
MARVELD2	FATE1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (87): MARVELD2 (Affinity Capture-RNA), MARVELD2 (Affinity Capture-RNA), MARVELD2 (Proximity Label-MS), MARVELD2 (Proximity Label-MS), MARVELD2 (Proximity Label-MS), MARVELD2 (Proximity Label-MS), STK38 (Affinity Capture-MS), TTL (Affinity Capture-MS), CTBS (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), BAIAP2L1 (Affinity Capture-MS), NDUFAF1 (Affinity Capture-MS), RAP2A (Affinity Capture-MS), ECSIT (Affinity Capture-MS), GAP43 (Affinity Capture-MS)

ESM2 similar proteins: A0JPA1, A4GG66, A4GVD1, A4IG66, A7YWH9, A9L8T6, B0VX73, B1MT31, F1NVK6, G5EBQ8, P18861, P28228, P28229, P36383, P91682, Q00M95, Q0IHQ3, Q0P5V9, Q11186, Q16625, Q28269, Q2HJ66, Q3UZP0, Q499S9, Q5BKX6, Q5RFS5, Q5YLM1, Q61146, Q62847, Q66IE4, Q6GMF8, Q6NZH5, Q6P6T5, Q6PIX5, Q6PJF5, Q6PYT3, Q6R4A8, Q6WQJ1, Q7TMB7, Q7ZXS7

Diamond homologs: F1MGG3, O00472, O08856, P55199, Q0IHQ3, Q3UKU1, Q3UZP0, Q5XFX8, Q80VR2, Q8N4S9, Q9HB65, Q9VW51, Q28793, Q91049, Q6P6T5, Q9H607, Q9PUN1, Q8VCR9, Q16625, Q28269, Q5RFS5, Q61146

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	14
Uncertain significance	126
Likely benign	53
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1196	NM_001038603.3(MARVELD2):c.1331+4_1331+7del	Pathogenic
1299311	NM_001038603.3(MARVELD2):c.608dup (p.Leu203fs)	Pathogenic
1446607	NM_001038603.3(MARVELD2):c.259A>T (p.Lys87Ter)	Pathogenic
1879627	NM_001038603.3(MARVELD2):c.1122_1123del (p.His374fs)	Pathogenic
228359	NM_001038603.3(MARVELD2):c.1331+1G>A	Pathogenic
2423538	NC_000005.9:g.(?68715213)(68737481_?)del	Pathogenic
2572552	NM_001038603.3(MARVELD2):c.666C>G (p.Tyr222Ter)	Pathogenic
2970042	NM_001038603.3(MARVELD2):c.949C>T (p.Arg317Ter)	Pathogenic
3601226	NM_001038603.3(MARVELD2):c.1295del (p.His432fs)	Pathogenic
3601227	NM_001038603.3(MARVELD2):c.1332-1del	Pathogenic
3601229	NM_001038603.3(MARVELD2):c.1374T>A (p.Tyr458Ter)	Pathogenic
3601230	NM_001038603.3(MARVELD2):c.1399del (p.Ser467fs)	Pathogenic
3601231	NM_001038603.3(MARVELD2):c.1467del (p.Val489_Met490insTer)	Pathogenic
3601234	NM_001038603.3(MARVELD2):c.670_694del (p.Leu224fs)	Pathogenic
3601235	NM_001038603.3(MARVELD2):c.683C>G (p.Ser228Ter)	Pathogenic
3683089	NM_001038603.3(MARVELD2):c.666C>A (p.Tyr222Ter)	Pathogenic
3764752	NM_001038603.3(MARVELD2):c.1058dup (p.Val354fs)	Pathogenic
4711659	NM_001038603.3(MARVELD2):c.111_114del (p.Glu38fs)	Pathogenic
620321	NM_001038603.3(MARVELD2):c.1160C>G (p.Ser387Ter)	Pathogenic
620515	NM_001038603.3(MARVELD2):c.866G>A (p.Trp289Ter)	Pathogenic
817776	NM_001038603.3(MARVELD2):c.799_800del (p.Thr267fs)	Pathogenic
996714	NM_001038603.3(MARVELD2):c.1138C>T (p.Gln380Ter)	Pathogenic
1185091	NM_001038603.3(MARVELD2):c.1122dup (p.Arg375Ter)	Likely pathogenic
1185092	NM_001038603.3(MARVELD2):c.1208_1211del (p.Arg403fs)	Likely pathogenic
1254896	NM_001038603.3(MARVELD2):c.490C>T (p.Arg164Ter)	Likely pathogenic
3075903	NM_001038603.3(MARVELD2):c.188C>A (p.Ser63Ter)	Likely pathogenic
3337268	NM_001038603.3(MARVELD2):c.1203del (p.Asp402fs)	Likely pathogenic
3601224	NM_001038603.3(MARVELD2):c.1123dup (p.Arg375fs)	Likely pathogenic
3601228	NM_001038603.3(MARVELD2):c.1363C>T (p.Arg455Ter)	Likely pathogenic
3601232	NM_001038603.3(MARVELD2):c.1512_1515del (p.Arg505fs)	Likely pathogenic

SpliceAI

930 predictions. Top by Δscore:

Variant	Effect	Δscore
5:69415168:CAGGT:C	donor_loss	1.0000
5:69415169:AGGT:A	donor_loss	1.0000
5:69415171:GTAA:G	donor_loss	1.0000
5:69432519:A:AG	acceptor_gain	1.0000
5:69432519:AACT:A	acceptor_gain	1.0000
5:69432520:A:G	acceptor_gain	1.0000
5:69432522:T:TA	acceptor_gain	1.0000
5:69432523:GCAG:G	acceptor_loss	1.0000
5:69432525:A:AG	acceptor_gain	1.0000
5:69432525:AGT:A	acceptor_gain	1.0000
5:69432525:AGTGT:A	acceptor_gain	1.0000
5:69432526:G:GA	acceptor_gain	1.0000
5:69432526:GT:G	acceptor_gain	1.0000
5:69432526:GTG:G	acceptor_gain	1.0000
5:69432526:GTGT:G	acceptor_gain	1.0000
5:69432526:GTGTG:G	acceptor_gain	1.0000
5:69432671:GTGGC:G	donor_gain	1.0000
5:69432672:TGGC:T	donor_gain	1.0000
5:69432673:GGC:G	donor_gain	1.0000
5:69432673:GGCG:G	donor_gain	1.0000
5:69432674:GC:G	donor_gain	1.0000
5:69432674:GCG:G	donor_gain	1.0000
5:69432676:G:GG	donor_gain	1.0000
5:69432680:GT:G	donor_gain	1.0000
5:69432908:T:G	acceptor_gain	1.0000
5:69432908:T:TA	acceptor_gain	1.0000
5:69432918:CTA:C	acceptor_loss	1.0000
5:69432920:A:AG	acceptor_gain	1.0000
5:69432920:AGA:A	acceptor_loss	1.0000
5:69432921:G:GC	acceptor_gain	1.0000

AlphaMissense

3649 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:69441572:T:C	L532P	0.999
5:69441582:A:C	K535N	0.999
5:69441582:A:T	K535N	0.999
5:69432974:T:C	F462L	0.998
5:69432976:C:A	F462L	0.998
5:69432976:C:G	F462L	0.998
5:69441581:A:T	K535I	0.998
5:69441584:T:C	L536P	0.998
5:69432954:G:C	R455P	0.997
5:69441597:G:C	K540N	0.997
5:69441597:G:T	K540N	0.997
5:69420037:G:C	D218H	0.996
5:69420250:T:A	W289R	0.996
5:69420250:T:C	W289R	0.996
5:69420388:T:A	C335S	0.996
5:69420388:T:C	C335R	0.996
5:69420389:G:A	C335Y	0.996
5:69420389:G:C	C335S	0.996
5:69432975:T:C	F462S	0.996
5:69432995:T:G	Y469D	0.996
5:69441580:A:G	K535E	0.996
5:69441584:T:A	L536H	0.996
5:69420346:T:C	C321R	0.995
5:69420390:C:G	C335W	0.995
5:69433005:T:C	L472P	0.995
5:69441560:G:C	R528P	0.995
5:69420013:T:C	C210R	0.994
5:69420038:A:C	D218A	0.994
5:69420038:A:T	D218V	0.994
5:69420048:G:C	W221C	0.994

dbSNP variants (sampled 300 via entrez): RS1000101068 (5:69430120 C>T), RS1000106111 (5:69417718 T>C,G), RS1000125667 (5:69440238 A>C,G), RS1000136008 (5:69434973 G>A), RS1000209913 (5:69426150 G>A), RS1000209968 (5:69434680 C>A), RS1000429938 (5:69442278 C>A), RS1000474262 (5:69436563 T>C), RS1000483771 (5:69426459 T>C), RS1000542533 (5:69436213 G>A), RS1000757201 (5:69428958 T>A,C), RS1000764389 (5:69433588 T>A), RS1000813810 (5:69426629 G>A,C), RS1000831798 (5:69420070 C>G), RS1000842332 (5:69415030 T>C)

Disease associations

OMIM: gene MIM:610572 | disease phenotypes: MIM:610153, MIM:128600, MIM:615349, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 49	Strong	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 (6): autosomal recessive nonsyndromic hearing loss 49 (MONDO:0012420), ear malformation (MONDO:0007500), Ehlers-Danlos syndrome, spondylodysplastic type, 2 (MONDO:0014139), hearing loss disorder (MONDO:0005365), hearing loss, autosomal recessive (MONDO:0019588), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (5): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic deafness (Orphanet:96210), B3GALT6-related spondylodysplastic Ehlers-Danlos syndrome (Orphanet:536467), B4GALT7-related spondylodysplastic Ehlers-Danlos syndrome (Orphanet:75496), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000399	Prelingual sensorineural hearing impairment
HP:0003577	Congenital onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010173_72	Triglyceride levels	3.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

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.)
C565717	Deafness, Autosomal Recessive 49 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	3
Smoke	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol A	increases expression, decreases expression	1
beta-lapachone	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	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
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Ethyl Methanesulfonate	decreases expression	1
Folic Acid	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	increases expression	1
Triclosan	decreases expression	1
Vanadates	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases expression	1
Lithium Chloride	increases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

10 cell lines: 10 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_CZ76	GM20173	Transformed cell line	Male
CVCL_CZ77	GM20191	Transformed cell line	Male
CVCL_DB96	GM20188	Transformed cell line	Male
CVCL_DB97	GM20192	Transformed cell line	Male
CVCL_DB98	GM20196	Transformed cell line	Female
CVCL_GS89	GM20172	Transformed cell line	Female
CVCL_GS92	GM20189	Transformed cell line	Male
CVCL_GS93	GM20190	Transformed cell line	Male
CVCL_GS94	GM20193	Transformed cell line	Male
CVCL_GS95	GM20197	Transformed cell line	Female

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
NCT06431698	Not specified	UNKNOWN	CORRECTION OF EAR DEFORMITIES IN NEWBORNS BY MODELING, COMPARISON OF TWO PROTOCOLS
NCT07154667	Not specified	RECRUITING	Evaluation of the Auryzon™ EAR 2.0 System in Ear Reconstruction
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