TRIOBP

Summary

TRIOBP (TRIO and F-actin binding protein, HGNC:17009) is a protein-coding gene on chromosome 22q13.1, encoding TRIO and F-actin-binding protein (Q9H2D6). Regulates actin cytoskeletal organization, cell spreading and cell contraction by directly binding and stabilizing filamentous F-actin and prevents its depolymerization.

This gene encodes a protein with an N-terminal pleckstrin homology domain and a C-terminal coiled-coil region. The protein interacts with trio, which is involved with neural tissue development and controlling actin cytoskeleton organization, cell motility and cell growth. The protein also associates with F-actin and stabilizes F-actin structures. Mutations in this gene have been associated with a form of autosomal recessive nonsyndromic deafness. Multiple alternatively spliced transcript variants that would encode different isoforms have been found for this gene, however some transcripts may be subject to nonsense-mediated decay (NMD).

Source: NCBI Gene 11078 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 24
• Clinical variants (ClinVar): 1,056 total — 63 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 3
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001039141

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17009
Approved symbol	TRIOBP
Name	TRIO and F-actin binding protein
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	HRIHFB2122, KIAA1662, Tara, TAP68
Ensembl gene	ENSG00000100106
Ensembl biotype	protein_coding
OMIM	609761
Entrez	11078

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000331103, ENST00000344404, ENST00000403663, ENST00000407319, ENST00000413051, ENST00000417857, ENST00000418339, ENST00000428075, ENST00000452519, ENST00000492485, ENST00000644935

RefSeq mRNA: 3 — MANE Select: NM_001039141 NM_001039141, NM_007032, NM_138632

CCDS: CCDS33644, CCDS43015, CCDS43016

Canonical transcript exons

ENST00000644935 — 24 exons

Exon	Start	End
ENSE00001883296	37773783	37776556
ENSE00003459424	37768074	37768176
ENSE00003468672	37754877	37754984
ENSE00003474276	37723185	37726503
ENSE00003497960	37769262	37769375
ENSE00003522943	37734399	37735442
ENSE00003526238	37759154	37759264
ENSE00003532228	37701306	37701479
ENSE00003541659	37765670	37765817
ENSE00003550994	37755550	37755659
ENSE00003552790	37771650	37771736
ENSE00003557777	37713210	37713411
ENSE00003558470	37755101	37755190
ENSE00003561657	37733298	37733412
ENSE00003568671	37710427	37710566
ENSE00003583608	37740895	37741032
ENSE00003598474	37697588	37697696
ENSE00003598789	37757613	37758138
ENSE00003600180	37772601	37772764
ENSE00003619120	37751772	37751828
ENSE00003633290	37715763	37715934
ENSE00003673922	37769028	37769187
ENSE00003688815	37738642	37738719
ENSE00003823279	37697048	37697089

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.8900 / max 174.6438, expressed in 1791 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192187	15.5231	1787
192186	2.0795	437
192185	0.1940	73
192188	0.0934	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	98.05	gold quality
cervix squamous epithelium	UBERON:0006922	97.46	gold quality
apex of heart	UBERON:0002098	96.94	gold quality
tongue squamous epithelium	UBERON:0006919	96.94	gold quality
heart right ventricle	UBERON:0002080	96.77	gold quality
stromal cell of endometrium	CL:0002255	96.75	gold quality
cauda epididymis	UBERON:0004360	96.61	gold quality
tendon of biceps brachii	UBERON:0008188	96.57	gold quality
left uterine tube	UBERON:0001303	96.52	gold quality
ectocervix	UBERON:0012249	96.37	gold quality
endocervix	UBERON:0000458	96.17	gold quality
right coronary artery	UBERON:0001625	96.02	gold quality
parotid gland	UBERON:0001831	96.00	gold quality
sural nerve	UBERON:0015488	95.99	gold quality
decidua	UBERON:0002450	95.89	gold quality
myometrium	UBERON:0001296	95.79	gold quality
cervix epithelium	UBERON:0004801	95.77	gold quality
placenta	UBERON:0001987	95.74	gold quality
uterine cervix	UBERON:0000002	95.71	gold quality
lower esophagus	UBERON:0013473	95.69	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.68	gold quality
esophagus mucosa	UBERON:0002469	95.63	gold quality
cardiac ventricle	UBERON:0002082	95.56	gold quality
esophagus	UBERON:0001043	95.54	gold quality
lower esophagus mucosa	UBERON:0035834	95.54	gold quality
right atrium auricular region	UBERON:0006631	95.53	gold quality
heart left ventricle	UBERON:0002084	95.52	gold quality
body of uterus	UBERON:0009853	95.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.48	gold quality
superficial temporal artery	UBERON:0001614	95.44	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.28
E-GEOD-135922	yes	10.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

99 targeting TRIOBP, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6755-5P	99.95	65.59	464
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-8082	99.95	67.27	1170
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6756-5P	99.82	67.97	2466

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 19)

• Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness. (PMID:16385457)
• Mutations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss. (PMID:16385458)
• All these findings suggest that HECTD3 may facilitate cell cycle progression via regulating ubiquitination and degradation of Tara. (PMID:18194665)
• Data show that 4-oxo-4-HPR inhibited tubulin polymerization and modulated gene expression of spindle aberration associated genes Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp. (PMID:19996280)
• the centrosomal localization of Tara depended on the Thr-457 phosphorylation and the kinase activity of Plk1. (PMID:22820163)
• TAP68 functions in mediating TRF1-tankyrase 1 localization to the centrosome and in mitotic regulation (PMID:24692559)
• High TRIOBP expression is associated with pancreatic cancer. (PMID:25130170)
• TRIOBP-1 aggregates are implicated for the first time as a biological element of the neuropathology of a subset of chronic mental illness (PMID:25333879)
• Results reveal that Tara forms a functional complex with Ndel1 and alters its intracellular distribution. The Ndel1-Tara complex plays a role in regulating actin cytoskeleton organization, which is critical for cell migration. (PMID:27546710)
• We discovered two genome-wide significant SNPs. The first was novel and near ISG20. The second was in TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. Motivated by our TRIOBP results, we also looked at exons in known hearing loss genes, and identified two additional SNPs, rs2877561 in ILDR1 and rs9493672 in EYA4 (at a significance threshold adjusted for number of SNPs in those regions). (PMID:27764096)
• Case Reports: novel TRIOBP mutations associated with moderate, stable hereditary hearing impairment. (PMID:28089734)
• TRIOBP-1 aggregation, therefore, appears to occur through one or more specific cellular mechanisms, which therefore have the potential to be of physiological relevance for the biological process underlying the development of chronic mental illness. (PMID:28438837)
• Based on whole exome analysis, we identified two TRIOBP pathogenic variants (c.802_805delCAGG, p.Gln268Leufs*610 and c.5014G>T, p.Gly1672*, the first of which was novel) causative of nonsyndromic, peri- to postlingual, moderate-to-severe hearing loss in three siblings from a Polish family. (PMID:29197352)
• TRIOBP-1 overexpression caused intracellular co-sequestration of hERG signal, reduced native IKr and disrupted action potential repolarization. (PMID:29507111)
• roles of TRIO and F-actin-binding protein in human diseases (PMID:29890989)
• Elucidation of repeat motifs R1- and R2-related TRIOBP variants in autosomal recessive nonsyndromic hearing loss DFNB28 among indigenous South African individuals. (PMID:36029164)
• TRIOBP-1 Protein Aggregation Exists in Both Major Depressive Disorder and Schizophrenia, and Can Occur through Two Distinct Regions of the Protein. (PMID:36232351)
• SYMPTOM SEVERITY IN SCHIZOPHRENIA PATIENTS WITH NPAS3, DYSBINDIN-1 AND/OR TRIOBP PROTEIN PATHOLOGY IN THEIR BLOOD SERUM: A PANSS-BASED FOLLOW UP STUDY. (PMID:37480305)
• TRIOBP modulates beta-catenin signaling by regulation of miR-29b in idiopathic pulmonary fibrosis. (PMID:38157020)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	triobpb	ENSDARG00000006385
danio_rerio	triobpa	ENSDARG00000075870
mus_musculus	Triobp	ENSMUSG00000033088
rattus_norvegicus	Triobp	ENSRNOG00000059015
drosophila_melanogaster	osp	FBGN0003016
caenorhabditis_elegans	F10G8.8	WBGENE00008666

Paralogs (1): MPRIP (ENSG00000133030)

Protein

Protein identifiers

TRIO and F-actin-binding protein — Q9H2D6 (reviewed: Q9H2D6)

Alternative names: Protein Tara, TRF1-associated protein of 68 kDa, Trio-associated repeat on actin

All UniProt accessions (7): Q9H2D6, F6TR96, F6WMF4, F6WYE2, H0Y5J9, H0Y5T8, H7BXW4

UniProt curated annotations — full annotation on UniProt →

Function. Regulates actin cytoskeletal organization, cell spreading and cell contraction by directly binding and stabilizing filamentous F-actin and prevents its depolymerization. May also serve as a linker protein to recruit proteins required for F-actin formation and turnover. Essential for correct mitotic progression. Plays a pivotal role in the formation of stereocilia rootlets. Plays a pivotal role in the formation of stereocilia rootlets.

Subunit / interactions. Isoform 1 forms aggregates. Isoform 1 binds to TRIO and F-actin. Isoform 1 may also interact with myosin II. Interacts with HECTD3. Interacts with PJVK. Interacts with TERF1; mediates TERF1 localization to the centrosome.

Subcellular location. Nucleus Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Midbody. Chromosome. Telomere.

Tissue specificity. Widely expressed. Highly expressed in heart and placenta. Expressed in fetal brain, retina and cochlea but is not detectable in the other tissues.

Post-translational modifications. Ubiquitinated by HECTD3, leading to its degradation by the proteasome. Phosphorylation at Thr-457 by PLK1 ensures mitotic progression and is essential for accurate chromosome segregation. Phosphorylation at residues Thr-221 and Thr-457 by kinase NEK2A and PLK1 coordinates TERF1 translocation from telomere to spindle pole.

Disease relevance. Deafness, autosomal recessive, 28 (DFNB28) [MIM:609823] 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.

Domain organisation. Contains at least 2 actin-binding sites per coiled-coil dimer.

Miscellaneous. Insoluble aggregates is found in the brain of schizophrenia patients. Produced by alternative promoter usage. Produced by alternative promoter usage. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 2. Produced by alternative splicing of isoform 2. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9H2D6-1	2, TRIOBP-6	yes
Q9H2D6-2	3, Long isoform
Q9H2D6-3	4, TRIOBP-5
Q9H2D6-4	5, TRIOBP-4
Q9H2D6-5	1, TRIOBP-1, TAP68, TARA
Q9H2D6-6	6
Q9H2D6-7	7

RefSeq proteins (3): NP_001034230, NP_008963, NP_619538 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR039597	M-RIP_PH	Domain
IPR052223	Actin_Cytoskeleton_Reg	Family

Pfam: PF00169

UniProt features (84 total): compositionally biased region 33, splice variant 11, sequence conflict 10, sequence variant 9, region of interest 7, modified residue 6, mutagenesis site 4, coiled-coil region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2D6-F1	40.77	0.10

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): 1796, 1930, 1949, 1955, 221, 457

Mutagenesis-validated functional residues (4):

Position	Phenotype
221	does not affect interaction with terf1. remains associated with terf1 at the telomere in late prometaphase cells.
221	abolishes interaction with terf1.
457	prevents the localization of terf1 to the centrosome.
457	does not affect interaction with terf1.

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: 258 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GCACCTT_MIR18A_MIR18B, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_NEUROGENESIS, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_SUBSTRATE_ADHESION_DEPENDENT_CELL_SPREADING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (6): sensory perception of sound (GO:0007605), actin modification (GO:0030047), barbed-end actin filament capping (GO:0051016), cell division (GO:0051301), auditory receptor cell stereocilium organization (GO:0060088), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026)

GO Molecular Function (5): small GTPase binding (GO:0031267), ubiquitin protein ligase binding (GO:0031625), myosin II binding (GO:0045159), actin filament binding (GO:0051015), actin binding (GO:0003779)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), centrosome (GO:0005813), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), midbody (GO:0030496), stereocilium base (GO:0120044), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

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
cellular anatomical structure	3
intracellular membraneless organelle	2
sensory perception of mechanical stimulus	1
actin cytoskeleton organization	1
protein modification process	1
actin filament capping	1
cellular process	1
auditory receptor cell morphogenesis	1
inner ear receptor cell stereocilium organization	1
positive regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
GTPase binding	1
ubiquitin-like protein ligase binding	1
myosin binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
centriole	1
microtubule organizing center	1
cell-substrate junction	1
cytoskeleton	1
stereocilium	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIOBP	TPRN	Q4KMQ1	671
TRIOBP	MYO15A	Q9UKN7	669
TRIOBP	ESPN	B1AK53	633
TRIOBP	TMC1	Q8TDI8	610
TRIOBP	CDH23	Q9H251	609
TRIOBP	LOXHD1	Q8IVV2	609
TRIOBP	TMIE	Q8NEW7	595
TRIOBP	MYO7A	P78427	594
TRIOBP	PLEK2	Q9NYT0	589
TRIOBP	MYO6	Q9UM54	584
TRIOBP	TMPRSS3	P57727	583
TRIOBP	OTOF	Q9HC10	582
TRIOBP	STRC	Q7RTU9	582
TRIOBP	OTOA	Q7RTW8	582
TRIOBP	SLC26A4	O43511	580

IntAct

100 interactions, top by confidence:

A	B	Type	Score
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CB	CCDC85C	psi-mi:“MI:2364”(proximity)	0.750
PACSIN1	COBL	psi-mi:“MI:0914”(association)	0.750
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
TRIOBP	FXR1	psi-mi:“MI:0915”(physical association)	0.550
KIAA1328	APC	psi-mi:“MI:0914”(association)	0.550
PACSIN3	COBL	psi-mi:“MI:0914”(association)	0.530
JPH4	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
FXR1	ORC2	psi-mi:“MI:0914”(association)	0.530
PSMC3	PSMD11	psi-mi:“MI:0914”(association)	0.530
KXD1	TRAK2	psi-mi:“MI:0914”(association)	0.530
PACSIN2	COBLL1	psi-mi:“MI:0914”(association)	0.530
PACSIN3	COBLL1	psi-mi:“MI:0914”(association)	0.530
BORCS6	HSBP1	psi-mi:“MI:0914”(association)	0.530
NDC80	HIP1R	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
PPP1R12A	PPP1R12B	psi-mi:“MI:2364”(proximity)	0.420
Plk1		psi-mi:“MI:0915”(physical association)	0.400
PCNA	TRIOBP	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (179): TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Co-fractionation), TRIOBP (Proximity Label-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS), TRIOBP (Affinity Capture-MS)

ESM2 similar proteins: A0A087WUL8, A0A0J9YWL9, A0A0J9YY54, A0A0U1RQI7, A6NJ88, A6QL64, B4DH59, D3ZVV1, E9Q6E9, F1LWT0, O04492, O88799, P0DKJ7, P0DKJ8, P0DKL2, P0DPF3, P18583, P53353, Q08AG5, Q0P6D6, Q2EG98, Q3BBV2, Q4ZJZ1, Q5HY64, Q5JPF3, Q5QGU6, Q5TAG4, Q5TI25, Q5XHX6, Q6P3W6, Q6P902, Q6XPR3, Q6ZQX7, Q86T75, Q86VE3, Q86VQ3, Q8N2N9, Q8N660, Q8N693, Q96EQ9

Diamond homologs: B6RSP1, P97434, Q6IQ23, Q6WCQ1, Q7TQG1, Q99KW3, Q9ERE6, Q9H2D6, Q9HAU0, Q9Y2H5, P60669, Q27421, Q3UIL6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PLK1	up-regulates	TRIOBP	phosphorylation
HECTD3	“down-regulates quantity by destabilization”	TRIOBP	polyubiquitination
GNAQ	“up-regulates activity”	TRIOBP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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
Defective CFTR causes cystic fibrosis	5	12.9×	6e-03
SCF(Skp2)-mediated degradation of p27/p21	5	12.2×	6e-03
Constitutive Signaling by Aberrant PI3K in Cancer	7	10.4×	2e-03
Clathrin-mediated endocytosis	9	9.0×	4e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	7	8.0×	6e-03
PIP3 activates AKT signaling	8	6.3×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of endocytosis	5	22.5×	2e-03
axonogenesis	6	9.0×	1e-02
actin filament organization	8	8.9×	2e-03
cell migration	9	5.2×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

1056 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	63
Likely pathogenic	28
Uncertain significance	450
Likely benign	308
Benign	83

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034395	NM_001039141.3(TRIOBP):c.3232dup (p.Arg1078fs)	Pathogenic
1174531	NM_001039141.3(TRIOBP):c.3214dup (p.Arg1072fs)	Pathogenic
1185086	NM_001039141.3(TRIOBP):c.1342C>T (p.Arg448Ter)	Pathogenic
1185656	NM_001039141.3(TRIOBP):c.3672_3673del (p.Arg1225fs)	Pathogenic
1415075	NM_001039141.3(TRIOBP):c.1420C>T (p.Arg474Ter)	Pathogenic
1426470	NM_001039141.3(TRIOBP):c.6260del (p.Glu2087fs)	Pathogenic
1455452	NM_001039141.3(TRIOBP):c.1222C>T (p.Gln408Ter)	Pathogenic
1490	NM_001039141.3(TRIOBP):c.1039C>T (p.Arg347Ter)	Pathogenic
1491	NM_001039141.3(TRIOBP):c.1741C>T (p.Gln581Ter)	Pathogenic
1492	NM_001039141.3(TRIOBP):c.889C>T (p.Gln297Ter)	Pathogenic
1493	NM_001039141.3(TRIOBP):c.2362C>T (p.Arg788Ter)	Pathogenic
1495	NM_001039141.3(TRIOBP):c.3349C>T (p.Arg1117Ter)	Pathogenic
1496	NM_001039141.3(TRIOBP):c.3202_3203del (p.Asp1069fs)	Pathogenic
165613	NM_001039141.3(TRIOBP):c.6598C>T (p.Arg2200Ter)	Pathogenic
1908361	NM_001039141.3(TRIOBP):c.4987dup (p.Gln1663fs)	Pathogenic
1950842	NM_001039141.3(TRIOBP):c.2548C>T (p.Gln850Ter)	Pathogenic
2009525	NM_001039141.3(TRIOBP):c.3718del (p.Leu1240fs)	Pathogenic
2092311	NM_001039141.3(TRIOBP):c.2472del (p.Arg825fs)	Pathogenic
2159885	NM_001039141.3(TRIOBP):c.4294G>T (p.Glu1432Ter)	Pathogenic
2181131	NM_001039141.3(TRIOBP):c.1960C>T (p.Arg654Ter)	Pathogenic
2423539	NC_000022.10:g.(?38111750)(38111961_?)del	Pathogenic
2445671	NM_001039141.3(TRIOBP):c.1783C>T (p.Arg595Ter)	Pathogenic
2445672	NM_001039141.3(TRIOBP):c.1861C>T (p.Arg621Ter)	Pathogenic
2445673	NM_001039141.3(TRIOBP):c.2581C>T (p.Arg861Ter)	Pathogenic
2814660	NM_001039141.3(TRIOBP):c.5300_5301del (p.Leu1767fs)	Pathogenic
2908067	NM_001039141.3(TRIOBP):c.1342del (p.Arg448fs)	Pathogenic
2979806	NM_001039141.3(TRIOBP):c.3295C>T (p.Gln1099Ter)	Pathogenic
2982427	NM_001039141.3(TRIOBP):c.3616_3617del (p.Leu1206fs)	Pathogenic
3255083	NM_001039141.3(TRIOBP):c.2758C>T (p.Arg920Ter)	Pathogenic
3358699	NM_001039141.3(TRIOBP):c.3833dup (p.Pro1279fs)	Pathogenic

SpliceAI

2384 predictions. Top by Δscore:

Variant	Effect	Δscore
22:37751767:CACA:C	acceptor_loss	1.0000
22:37751770:A:AG	acceptor_gain	1.0000
22:37751770:AGCCC:A	acceptor_gain	1.0000
22:37751771:G:GA	acceptor_gain	1.0000
22:37751771:GC:G	acceptor_gain	1.0000
22:37751771:GCC:G	acceptor_gain	1.0000
22:37751771:GCCC:G	acceptor_gain	1.0000
22:37751771:GCCCG:G	acceptor_gain	1.0000
22:37751824:GAGAG:G	donor_gain	1.0000
22:37751826:GAG:G	donor_gain	1.0000
22:37751827:AGGTA:A	donor_loss	1.0000
22:37751828:GGT:G	donor_loss	1.0000
22:37751829:G:GA	donor_loss	1.0000
22:37751829:G:GG	donor_gain	1.0000
22:37751830:T:A	donor_loss	1.0000
22:37755096:TCCAG:T	acceptor_loss	1.0000
22:37755097:CCA:C	acceptor_loss	1.0000
22:37755098:CAGGC:C	acceptor_loss	1.0000
22:37755099:A:AG	acceptor_gain	1.0000
22:37755099:A:AT	acceptor_loss	1.0000
22:37755100:G:GG	acceptor_gain	1.0000
22:37755191:G:GG	donor_gain	1.0000
22:37755575:C:A	acceptor_gain	1.0000
22:37755653:TCACC:T	donor_gain	1.0000
22:37755657:CAAGT:C	donor_loss	1.0000
22:37755659:AGTA:A	donor_loss	1.0000
22:37755660:G:C	donor_loss	1.0000
22:37755660:GTAC:G	donor_gain	1.0000
22:37758135:GGAG:G	donor_gain	1.0000
22:37758136:GAGG:G	donor_gain	1.0000

AlphaMissense

15185 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:37754931:T:C	F1812L	1.000
22:37754932:T:C	F1812S	1.000
22:37754933:T:A	F1812L	1.000
22:37754933:T:G	F1812L	1.000
22:37754953:T:C	L1819P	1.000
22:37755180:T:C	F1856S	1.000
22:37755186:T:C	I1858T	1.000
22:37755604:T:A	W1878R	1.000
22:37755604:T:C	W1878R	1.000
22:37751796:G:A	G1783R	0.999
22:37751796:G:C	G1783R	0.999
22:37751799:T:A	W1784R	0.999
22:37751799:T:C	W1784R	0.999
22:37751801:G:C	W1784C	0.999
22:37751801:G:T	W1784C	0.999
22:37754916:T:A	W1807R	0.999
22:37754916:T:C	W1807R	0.999
22:37754918:G:C	W1807C	0.999
22:37754918:G:T	W1807C	0.999
22:37754928:T:A	W1811R	0.999
22:37754928:T:C	W1811R	0.999
22:37754953:T:A	L1819H	0.999
22:37754958:T:G	Y1821D	0.999
22:37754961:T:G	Y1822D	0.999
22:37755147:T:A	V1845D	0.999
22:37755177:G:A	G1855D	0.999
22:37755179:T:C	F1856L	0.999
22:37755181:C:A	F1856L	0.999
22:37755181:C:G	F1856L	0.999
22:37755183:A:C	Q1857P	0.999

dbSNP variants (sampled 300 via entrez): RS1000005596 (22:37715401 G>A), RS1000035088 (22:37715101 G>A), RS1000081633 (22:37727879 C>T), RS1000170782 (22:37731140 C>G), RS1000173020 (22:37769929 A>G), RS1000182101 (22:37695178 G>A), RS1000237406 (22:37770629 G>A,T), RS1000259168 (22:37738851 G>A), RS1000300243 (22:37700377 A>G), RS1000323754 (22:37719913 G>T), RS1000369845 (22:37731322 T>C,G), RS1000398077 (22:37726044 C>G,T), RS1000435582 (22:37770875 G>T), RS1000475846 (22:37710318 C>A,T), RS1000493379 (22:37767582 C>T)

Disease associations

OMIM: gene MIM:609761 | disease phenotypes: MIM:609823, MIM:220290, MIM:607197, MIM:156000

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 28	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Definitive	AR

Mondo (5): autosomal recessive nonsyndromic hearing loss 28 (MONDO:0012355), hearing loss disorder (MONDO:0005365), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss, autosomal recessive (MONDO:0019588), Meniere disease (MONDO:0007972)

Orphanet (5): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic deafness (Orphanet:96210), Rare non-syndromic genetic deafness (Orphanet:87884), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003593	Infantile onset
HP:0008625	Severe sensorineural hearing impairment

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST002764_15	Optic cup area	5.000000e-06
GCST002764_9	Optic cup area	1.000000e-09
GCST003763_2	Age-related hearing impairment	2.000000e-09
GCST004137_14	Optic cup area	2.000000e-08
GCST004765_34	Total cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	7.000000e-07
GCST005580_263	Intraocular pressure	3.000000e-10
GCST005580_270	Intraocular pressure	5.000000e-10
GCST006394_64	Intraocular pressure	7.000000e-12
GCST006395_8	Glaucoma	5.000000e-06
GCST006412_133	Intraocular pressure	2.000000e-12
GCST006629_43	Pulse pressure	5.000000e-11
GCST007147_5	Lateral ventricular volume in normal aging	1.000000e-10
GCST008899_3	Adult hearing difficulty	5.000000e-12
GCST009432_6	Age-related hearing impairment (low/mid frequency)	3.000000e-06
GCST009723_35	Vertical cup-disc ratio (adjusted for vertical disc diameter)	5.000000e-14
GCST009724_107	Vertical cup-disc ratio (multi-trait analysis)	2.000000e-16
GCST009725_30	Intraocular pressure	6.000000e-14
GCST010703_11	Brain morphology (MOSTest)	9.000000e-10
GCST011438_32	Glaucoma (primary open-angle)	1.000000e-08
GCST012442_24	Age-related hearing impairment	3.000000e-07
GCST012442_41	Age-related hearing impairment	1.000000e-17
GCST90002379_171	Basophil count	6.000000e-11
GCST90011768_18	Glaucoma (primary open-angle)	8.000000e-07
GCST90011770_86	Glaucoma (primary open-angle)	1.000000e-18

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007806	total cholesterol change measurement
EFO:0004695	intraocular pressure measurement
EFO:0005763	pulse pressure measurement
EFO:0008487	lateral ventricle volume measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0004346	neuroimaging measurement
EFO:0005090	basophil count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008575	Meniere Disease	C09.218.568.217.500
C564609	Deafness, Autosomal Recessive (supp.)
C565218	Deafness, Autosomal Recessive 28 (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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, decreases expression	2
cobaltous chloride	decreases expression	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
cupric oxide	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
exemestane	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
monomethylarsonous acid	decreases expression	1
ICG 001	affects expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Microplastics	increases abundance, decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1

Cellosaurus cell lines

3 cell lines: 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DB95	GM20184	Transformed cell line	Male
CVCL_GS90	GM20182	Transformed cell line	Male
CVCL_GS91	GM20185	Transformed cell line	Male

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