Nonsyndromic genetic hearing loss

Summary

Nonsyndromic genetic hearing loss (MONDO:0019497) is a disease (an umbrella term covering 6 Mondo subtypes) caused by variants in ACTG1, CABP2, CDC14A, and 39 other genes, with 89 cohort genes and 1 clinical trial. The dominant Reactome pathway is Sensory processing of sound by outer hair cells of the cochlea (27 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: ACTG1 (GenCC Definitive), CABP2 (GenCC Definitive), CDC14A (GenCC Definitive), CDH23 (GenCC Definitive) (+38 more)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 89
• ClinVar variants: 319
• Phenotypes (HPO): 13
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000399	Prelingual sensorineural hearing impairment	Frequent (30-79%)
HP:0000408	Progressive sensorineural hearing impairment	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001963	Abnormal speech discrimination	Frequent (30-79%)
HP:0008596	Postlingual sensorineural hearing impairment	Frequent (30-79%)
HP:0011476	Profound sensorineural hearing impairment	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0005101	High-frequency hearing impairment	Occasional (5-29%)
HP:0007670	Abnormal vestibulo-ocular reflex	Occasional (5-29%)
HP:0011474	Childhood onset sensorineural hearing impairment	Occasional (5-29%)
HP:0012713	Moderate hearing impairment	Occasional (5-29%)
HP:0012714	Severe hearing impairment	Occasional (5-29%)
HP:0008573	Low-frequency sensorineural hearing impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	nonsyndromic genetic hearing loss
Mondo ID	MONDO:0019497
MeSH	C580334
Orphanet	87884
DOID	DOID:0050563
ICD-11	1154032108
UMLS	C5680182
MedGen	1830101
Is cancer (heuristic)	no

Also known as: familial deafness · isolated genetic deafness · non-syndromic genetic deafness · nonsyndromic deafness · nonsyndromic genetic deafness · nonsyndromic genetic hearing loss · nonsyndromic hearing loss

Data availability: 319 ClinVar variants · 97 ClinGen variant curations · 102 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › auditory system disorder › hearing disorder › hearing loss disorder › nonsyndromic genetic hearing loss

Related subtypes (10): Johanson-Blizzard syndrome, noise induced hearing loss, sudden hearing loss disorder, sensorineural hearing loss disorder, conductive hearing loss disorder, central hearing loss, X-linked deafness, auditory neuropathy, hearing loss, mixed conductive-sensorineural, drug-induced hearing loss

Subtypes (6): prelingual non-syndromic genetic hearing loss, postlingual non-syndromic genetic hearing loss, X-linked nonsyndromic hearing loss, autosomal dominant nonsyndromic hearing loss, hearing loss, autosomal recessive, nonsyndromic deafness, Y-linked

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

319 retrieved; paginated sample, class counts are floors:

80 pathogenic, 56 pathogenic/likely pathogenic, 52 likely pathogenic, 46 uncertain significance, 38 conflicting classifications of pathogenicity, 20 benign, 18 likely benign, 8 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
424815	NM_206933.2(USH2A):c.[240_241insGTAC];[3368A>G]		Pathogenic	no assertion criteria provided
18316	NM_001614.5(ACTG1):c.353A>T (p.Lys118Met)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446446	NM_022124.6(CDH23):c.6085C>T (p.Arg2029Trp)	CDH23	Pathogenic	reviewed by expert panel
4928	NM_022124.6(CDH23):c.719C>T (p.Pro240Leu)	CDH23	Pathogenic	reviewed by expert panel
6611	NM_004086.3(COCH):c.151C>T (p.Pro51Ser)	COCH	Pathogenic	reviewed by expert panel
978789	Single allele	CRYL1	Pathogenic	criteria provided, single submitter
1185589	NM_004100.5(EYA4):c.580+2T>C	EYA4	Pathogenic	criteria provided, single submitter
1185804	NM_004004.6(GJB2):c.104T>G (p.Ile35Ser)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158608	NM_004004.6(GJB2):c.632_633del (p.Cys211fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17000	NM_004004.6(GJB2):c.101T>C (p.Met34Thr)	GJB2	Pathogenic	reviewed by expert panel
17002	NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)	GJB2	Pathogenic	reviewed by expert panel
17003	NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17004	NM_004004.6(GJB2):c.35del (p.Gly12fs)	GJB2	Pathogenic	reviewed by expert panel
17005	NM_004004.6(GJB2):c.139G>T (p.Glu47Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17006	NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17007	NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17009	NM_004004.6(GJB2):c.427C>T (p.Arg143Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17010	NM_004004.6(GJB2):c.167del (p.Leu56fs)	GJB2	Pathogenic	reviewed by expert panel
17011	NM_004004.6(GJB2):c.223C>T (p.Arg75Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17014	NM_004004.6(GJB2):c.235del (p.Leu79fs)	GJB2	Pathogenic	reviewed by expert panel
17016	NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17017	NM_004004.6(GJB2):c.428G>A (p.Arg143Gln)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17023	NM_004004.6(GJB2):c.109G>A (p.Val37Ile)	GJB2	Pathogenic	reviewed by expert panel
17027	NM_004004.6(GJB2):c.224G>A (p.Arg75Gln)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17029	NM_004004.6(GJB2):c.-23+1G>A	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17032	NM_004004.6(GJB2):c.250G>C (p.Val84Leu)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
177735	NM_004004.6(GJB2):c.239A>C (p.Gln80Pro)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177737	NM_004004.6(GJB2):c.269dup (p.Val91fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1799567	NM_004004.6(GJB2):c.449del (p.Phe150fs)	GJB2	Pathogenic	no assertion criteria provided
188756	NM_004004.6(GJB2):c.246C>G (p.Ile82Met)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 608 · Orphanet: 149 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACTG1	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	9
CABP2	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	4
CDC14A	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	4
CDH23	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	8
CIB2	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	7
CLDN14	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	4
COCH	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	4
ESPN	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	12
ESRRB	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6
EYA4	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	7
GIPC3	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	5
GJB2	Definitive	Autosomal dominant	hearing loss disorder	26
GRHL2	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	14
GRXCR1	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6
ILDR1	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	5
KCNQ4	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 2A	6
LHFPL5	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	5
LOXHD1	Definitive	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 77	7
MARVELD2	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6
MPZL2	Definitive	Autosomal recessive	hearing loss, autosomal recessive 111	5
MSRB3	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6
MYH14	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 4A	9
MYO15A	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	5
MYO6	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 22	11
MYO7A	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	15
OTOA	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6
OTOG	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6
OTOGL	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	6
PCDH15	Definitive	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 23	9
PJVK	Definitive	Autosomal recessive	nonsyndromic genetic hearing loss	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TECTA	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TECTA	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TMPRSS3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:231169	Usher syndrome type 1
CDH23	Orphanet:2965	Prolactinoma
CDH23	Orphanet:314777	Familial isolated pituitary adenoma
CDH23	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDH23	Orphanet:91347	TSH-secreting pituitary adenoma
CDH23	Orphanet:96253	Cushing disease
CABP2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
RIPOR2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SLC44A4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ACTG1	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTG1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ACTG1	Orphanet:98942	Coloboma of choroid and retina
ACTG1	Orphanet:98944	Coloboma of iris
STRC	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
STRC	Orphanet:94064	Deafness-infertility syndrome
OTOA	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TMC1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TMC1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CCDC50	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GIPC3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
LHFPL5	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
COCH	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MYH14	Orphanet:397744	MYH14-related peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome
MYH14	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
LOXHD1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SYNE4	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
OTOGL	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
ILDR1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
DMXL2	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
DMXL2	Orphanet:453533	Polyendocrine-polyneuropathy syndrome
DMXL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CEACAM16	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CEACAM16	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
EYA4	Orphanet:217622	Sensorineural deafness with dilated cardiomyopathy
EYA4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJB6	Orphanet:189	Hidrotic ectodermal dysplasia
GJB6	Orphanet:477	KID syndrome
GJB6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TNC	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

89 cohort genes, 88 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	89

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TECTA	HGNC:11720	ENSG00000109927	O75443	Alpha-tectorin	gencc,clinvar
TMPRSS3	HGNC:11877	ENSG00000160183	P57727	Transmembrane protease serine 3	gencc,clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	gencc,clinvar
CABP2	HGNC:1385	ENSG00000167791	Q9NPB3	Calcium-binding protein 2	gencc,clinvar
RIPOR2	HGNC:13872	ENSG00000111913	Q9Y4F9	Rho family-interacting cell polarization regulator 2	gencc,clinvar
SLC44A4	HGNC:13941	ENSG00000204385	Q53GD3	Choline transporter-like protein 4	gencc,clinvar
ACTG1	HGNC:144	ENSG00000184009	P63261	Actin, cytoplasmic 2	gencc,clinvar
STRC	HGNC:16035	ENSG00000242866	Q7RTU9	Stereocilin	gencc,clinvar
OTOA	HGNC:16378	ENSG00000155719	Q7RTW8	Otoancorin	gencc,clinvar
TMC1	HGNC:16513	ENSG00000165091	Q8TDI8	Transmembrane channel-like protein 1	gencc,clinvar
CCDC50	HGNC:18111	ENSG00000152492	Q8IVM0	Coiled-coil domain-containing protein 50	gencc,clinvar
GIPC3	HGNC:18183	ENSG00000179855	Q8TF64	PDZ domain-containing protein GIPC3	gencc,clinvar
LHFPL5	HGNC:21253	ENSG00000197753	Q8TAF8	LHFPL tetraspan subfamily member 5 protein	gencc,clinvar
COCH	HGNC:2180	ENSG00000100473	O43405	Cochlin	gencc,clinvar
MYH14	HGNC:23212	ENSG00000105357	Q7Z406	Myosin-14	gencc,clinvar
LOXHD1	HGNC:26521	ENSG00000167210	Q8IVV2	Lipoxygenase homology domain-containing protein 1	gencc,clinvar
SYNE4	HGNC:26703	ENSG00000181392	Q8N205	Nesprin-4	gencc,clinvar
OTOGL	HGNC:26901	ENSG00000165899	Q3ZCN5	Otogelin-like protein	gencc,clinvar
ILDR1	HGNC:28741	ENSG00000145103	Q86SU0	Immunoglobulin-like domain-containing receptor 1	gencc,clinvar
DMXL2	HGNC:2938	ENSG00000104093	Q8TDJ6	DmX-like protein 2	gencc,clinvar
CEACAM16	HGNC:31948	ENSG00000213892	Q2WEN9	Cell adhesion molecule CEACAM16	gencc,clinvar
EYA4	HGNC:3522	ENSG00000112319	O95677	Protein phosphatase EYA4	gencc,clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	gencc,clinvar
GJB6	HGNC:4288	ENSG00000121742	O95452	Gap junction beta-6 protein	gencc,clinvar
TNC	HGNC:5318	ENSG00000041982	P24821	Tenascin	gencc,clinvar
KARS1	HGNC:6215	ENSG00000065427	Q15046	Lysine–tRNA ligase	gencc,clinvar
KCNQ4	HGNC:6298	ENSG00000117013	P56696	Potassium voltage-gated channel subfamily KQT member 4	gencc,clinvar
MYO15A	HGNC:7594	ENSG00000091536	Q9UKN7	Unconventional myosin-XV	gencc,clinvar
MYO6	HGNC:7605	ENSG00000196586	Q9UM54	Unconventional myosin-VI	gencc,clinvar
MYO7A	HGNC:7606	ENSG00000137474	Q13402	Unconventional myosin-VIIa	gencc,clinvar
OTOG	HGNC:8516	ENSG00000188162	Q6ZRI0	Otogelin	gencc,clinvar
POU3F4	HGNC:9217	ENSG00000196767	P49335	POU domain, class 3, transcription factor 4	gencc,clinvar
SLC26A5	HGNC:9359	ENSG00000170615	P58743	Prestin	gencc,clinvar
RDX	HGNC:9944	ENSG00000137710	P35241	Radixin	gencc,clinvar
ROR1	HGNC:10256	ENSG00000185483	Q01973	Inactive tyrosine-protein kinase transmembrane receptor ROR1	gencc
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gencc
SMPX	HGNC:11122	ENSG00000091482	Q9UHP9	Small muscular protein	gencc
THBS1	HGNC:11785	ENSG00000137801	P07996	Thrombospondin-1	gencc
TJP2	HGNC:11828	ENSG00000119139	Q9UDY2	Tight junction protein 2	gencc
USH1C	HGNC:12597	ENSG00000006611	Q9Y6N9	Harmonin	gencc
IKZF2	HGNC:13177	ENSG00000030419	Q9UKS7	Zinc finger protein Helios	gencc
ESPN	HGNC:13281	ENSG00000187017	B1AK53	Espin	gencc
MEPE	HGNC:13361	ENSG00000152595	Q9NQ76	Matrix extracellular phosphoglycoprotein	gencc
BDP1	HGNC:13652	ENSG00000145734	A6H8Y1	Transcription factor TFIIIB component B’’ homolog	gencc
PCDH15	HGNC:14674	ENSG00000150275	Q96QU1	Protocadherin-15	gencc
TMPRSS5	HGNC:14908	ENSG00000166682	Q9H3S3	Transmembrane protease serine 5	gencc
P2RX2	HGNC:15459	ENSG00000187848	Q9UBL9	P2X purinoceptor 2	gencc
OSBPL2	HGNC:15761	ENSG00000130703	Q9H1P3	Oxysterol-binding protein-related protein 2	gencc
SEZ6	HGNC:15955	ENSG00000063015	Q53EL9	Seizure protein 6 homolog	gencc
USH1G	HGNC:16356	ENSG00000182040	Q495M9	pre-mRNA splicing regulator USH1G	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TECTA	Alpha-tectorin	One of the major non-collagenous components of the tectorial membrane.
TMPRSS3	Transmembrane protease serine 3	Probable serine protease that plays a role in hearing.
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
CABP2	Calcium-binding protein 2	Required for sound encoding at inner hair cells (IHCs) synapses, likely via inhibition of the inactivation of voltage-gated calcium channel of type 1.3 (Cav1.3) in the IHCs.
RIPOR2	Rho family-interacting cell polarization regulator 2	Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization.
SLC44A4	Choline transporter-like protein 4	Choline transporter that plays a role in the choline-acetylcholine system and is required to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the prote…
ACTG1	Actin, cytoplasmic 2	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
STRC	Stereocilin	Essential to the formation of horizontal top connectors between outer hair cell stereocilia.
OTOA	Otoancorin	May act as an adhesion molecule.
TMC1	Transmembrane channel-like protein 1	Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.
CCDC50	Coiled-coil domain-containing protein 50	Involved in EGFR signaling.
GIPC3	PDZ domain-containing protein GIPC3	Required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion.
LHFPL5	LHFPL tetraspan subfamily member 5 protein	Auxiliary subunit of the mechanotransducer (MET) non-specific cation channel complex located at the tips of the shorter stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.
COCH	Cochlin	Plays a role in the control of cell shape and motility in the trabecular meshwork.
MYH14	Myosin-14	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
LOXHD1	Lipoxygenase homology domain-containing protein 1	Involved in hearing.
SYNE4	Nesprin-4	As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton.
ILDR1	Immunoglobulin-like domain-containing receptor 1	Maintains epithelial barrier function by recruiting MARVELD2/tricellulin to tricellular tight junctions (tTJs).
DMXL2	DmX-like protein 2	May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles.
CEACAM16	Cell adhesion molecule CEACAM16	Required for proper hearing, plays a role in maintaining the integrity of the tectorial membrane.
EYA4	Protein phosphatase EYA4	Tyrosine phosphatase that specifically dephosphorylates ‘Tyr-142’ of histone H2AX (H2AXY142ph). ‘Tyr-142’ phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair…
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
GJB6	Gap junction beta-6 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
TNC	Tenascin	Extracellular matrix protein implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity as well as neuronal regeneration.
KARS1	Lysine–tRNA ligase	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
KCNQ4	Potassium voltage-gated channel subfamily KQT member 4	Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of sensory cells excitability in the cochlea.
MYO15A	Unconventional myosin-XV	Myosins are actin-based motor molecules with ATPase activity.
MYO6	Unconventional myosin-VI	Myosins are actin-based motor molecules with ATPase activity.
MYO7A	Unconventional myosin-VIIa	Myosins are actin-based motor molecules with ATPase activity.
OTOG	Otogelin	Glycoprotein specific to acellular membranes of the inner ear.
POU3F4	POU domain, class 3, transcription factor 4	Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain.
SLC26A5	Prestin	Voltage-sensitive motor protein that drives outer hair cell (OHC) electromotility (eM) and participates in sound amplification in the hearing organ.
RDX	Radixin	Probably plays a crucial role in the binding of the barbed end of actin filaments to the plasma membrane.
ROR1	Inactive tyrosine-protein kinase transmembrane receptor ROR1	Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo.
RORA	Nuclear receptor ROR-alpha	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
SMPX	Small muscular protein	Plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.
THBS1	Thrombospondin-1	Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.
TJP2	Tight junction protein 2	Plays a role in tight junctions and adherens junctions.
USH1C	Harmonin	Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells.
IKZF2	Zinc finger protein Helios	Transcription factor, which stabilizes the noninflammatory phenotype of regulatory T cells (Tregs).
ESPN	Espin	Multifunctional actin-bundling protein.
MEPE	Matrix extracellular phosphoglycoprotein	Promotes renal phosphate excretion and inhibits intestinal phosphate absorption.
BDP1	Transcription factor TFIIIB component B’’ homolog	General activator of RNA polymerase III transcription.
PCDH15	Protocadherin-15	Calcium-dependent cell-adhesion protein.
TMPRSS5	Transmembrane protease serine 5	May play a role in hearing.
P2RX2	P2X purinoceptor 2	ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium.
OSBPL2	Oxysterol-binding protein-related protein 2	Intracellular transport protein that binds sterols and phospholipids and mediates lipid transport between intracellular compartments.
SEZ6	Seizure protein 6 homolog	May play a role in cell-cell recognition and in neuronal membrane signaling.
USH1G	pre-mRNA splicing regulator USH1G	Plays a role in pre-mRNA splicing by regulating the release and transfer of U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complexes from their assembly site in Cajal bodies to nuclear speckles, thereby contributing to the assemb…
WHRN	Whirlin	Involved in hearing and vision as member of the USH2 complex.

Protein-family classification

Druggable: 21 · Difficult: 19 · Unknown: 49 · Druggable fraction: 0.24

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	14	2.7×	0.007
Nuclear receptor	2	8.7×	0.145
Complement	1	3.0×	0.987
Antibody/Immunoglobulin	4	1.3×	0.987
Ion channel	1	1.2×	0.987
Protease	3	1.2×	0.987
Other/Unknown	49	1.0×	0.987
Phosphatase	1	0.9×	0.987
Transporter	1	0.9×	0.987
Kinase	2	0.6×	0.987
Enzyme (other)	4	0.5×	0.987
GPCR	2	0.5×	0.987
Transcription factor	5	0.5×	0.987

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TECTA	Other/Unknown	no		EGF, VWF_dom, ZP_dom
TMPRSS3	Protease	yes		SRCR, Trypsin_dom, Peptidase_S1A
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
CABP2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
RIPOR2	Other/Unknown	no		ARM-like, ARM-type_fold, RIPOR3
SLC44A4	Other/Unknown	no		Choline_transptr-like
ACTG1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
STRC	Other/Unknown	no		Stereocilin-rel, Stereocilin_LRR
OTOA	Other/Unknown	no		Stereocilin-rel
TMC1	Other/Unknown	no		TMC_dom, TMC
CCDC50	Other/Unknown	no		CCDC50_N, CCDC50
GIPC3	Scaffold/PPI	no		PDZ, GIPC1/2/3, PDZ_sf
LHFPL5	Other/Unknown	no		LHFPL
COCH	Other/Unknown	no		VWF_A, LCCL, vWFA_dom_sf
MYH14	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
LOXHD1	Other/Unknown	no		PLAT/LH2_dom, PLAT/LH2_dom_sf, Inner_ear_hair_cell_LOXHD
SYNE4	Other/Unknown	no		KASH, SYNE4
OTOGL	Other/Unknown	no		VWF_dom, VWF_type-D, TIL_dom
ILDR1	Antibody/Immunoglobulin	yes		Ig_sub, LISCH7, Ig-like_fold
DMXL2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, Rav1p_C
CEACAM16	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
EYA4	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N
GJB6	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
TNC	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
KARS1	Enzyme (other)	yes	6.1.1.6	Lys-tRNA-ligase_II, Aa-tRNA-synt_II, NA-bd_OB_tRNA
KCNQ4	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCNQ_C
MYO15A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, FERM_domain, MyTH4_dom
MYO6	Scaffold/PPI	no		Myosin_head_motor_dom-like, SH3_Myosin, Myosin_S1_N
MYO7A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, FERM_domain, MyTH4_dom
OTOG	Other/Unknown	no		EGF, VWF_dom, VWF_type-D
POU3F4	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
SLC26A5	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
RDX	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, Moesin_tail_sf
ROR1	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
SMPX	Other/Unknown	no		Chisel
THBS1	Other/Unknown	no		EGF, TSP1_rpt, VWF_dom
TJP2	Scaffold/PPI	no		SH3_domain, PDZ, ZO
USH1C	Scaffold/PPI	no		PDZ, Harmonin_N, PDZ_sf
IKZF2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF
ESPN	Scaffold/PPI	no		Ankyrin_rpt, WH2_dom, Ankyrin_rpt-contain_sf
MEPE	Other/Unknown	no		MEPE
BDP1	Transcription factor	no		SANT/Myb, Homeodomain-like_sf, TFIIIB_B’’_Myb
PCDH15	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
TMPRSS5	Protease	yes		SRCR, Trypsin_dom, Peptidase_S1A
P2RX2	Other/Unknown	no		P2X_purnocptor, P2X2_purnocptor, P2X_extracellular_dom_sf
OSBPL2	Other/Unknown	no		Oxysterol-bd, Oxysterol-bd_CS, OSBP_sf
SEZ6	Complement	yes		Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf
USH1G	Scaffold/PPI	no		SAM, Ankyrin_rpt, SAM/pointed_sf

Expression context

Cohort genes with no expression data: 0.

76 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	5
broad (>20)	84
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	10
ventricular zone	6
mucosa of transverse colon	6
left testis	6
primordial germ cell in gonad	6
skeletal muscle tissue of biceps brachii	5
oocyte	4
secondary oocyte	4
right uterine tube	4
monocyte	4
ileal mucosa	4
cerebellar cortex	4
right hemisphere of cerebellum	4
buccal mucosa cell	4
body of pancreas	4
right testis	4
colonic epithelium	4
gingival epithelium	4
right adrenal gland cortex	4
parotid gland	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TECTA	166		marker	oocyte, secondary oocyte, parotid gland
TMPRSS3	177	tissue_specific	marker	pancreatic ductal cell, right uterine tube, bronchial epithelial cell
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary
CABP2	13	tissue_specific	marker	parotid gland, myocardium, skeletal muscle tissue of biceps brachii
RIPOR2	250	broad	marker	blood, monocyte, mononuclear cell
SLC44A4	130	tissue_specific	marker	mucosa of transverse colon, right uterine tube, rectum
ACTG1	288	ubiquitous	marker	ileal mucosa, ventricular zone, amniotic fluid
STRC	167		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
OTOA	86		yes	primordial germ cell in gonad, left testis, testis
TMC1	150		marker	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, primordial germ cell in gonad
CCDC50	256	ubiquitous	marker	oviduct epithelium, ileal mucosa, calcaneal tendon
GIPC3	157	tissue_specific	yes	apex of heart, stromal cell of endometrium, lower esophagus muscularis layer
LHFPL5	161	tissue_specific	marker	body of pancreas, male germ line stem cell (sensu Vertebrata) in testis, pancreas
COCH	272	broad	marker	buccal mucosa cell, saphenous vein, skeletal muscle tissue of biceps brachii
MYH14	227	broad	marker	mucosa of transverse colon, ileal mucosa, gastrocnemius
LOXHD1	135	tissue_specific	marker	left testis, right testis, testis
SYNE4	167	broad	marker	pancreatic ductal cell, cerebellar cortex, cerebellar hemisphere
OTOGL	152	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right atrium auricular region, cardiac atrium
ILDR1	140	broad	marker	corpus epididymis, kidney epithelium, nasal cavity epithelium
DMXL2	269	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
CEACAM16	26		yes	colonic epithelium, body of pancreas, mucosa of transverse colon
EYA4	208	broad	marker	biceps brachii, skeletal muscle tissue of biceps brachii, seminal vesicle
GJB2	196	broad	marker	gingival epithelium, gingiva, penis
GJB6	187	broad	marker	upper arm skin, gingiva, gingival epithelium
TNC	272	ubiquitous	marker	saphenous vein, tibial artery, popliteal artery
KARS1	299	ubiquitous	marker	gingival epithelium, parietal pleura, endometrium epithelium
KCNQ4	182	broad	marker	pigmented layer of retina, lower esophagus muscularis layer, lower esophagus
MYO15A	170	tissue_specific	marker	pituitary gland, adenohypophysis, left testis
MYO6	278	ubiquitous	marker	amniotic fluid, medial globus pallidus, corpus callosum
MYO7A	186	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 257.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
THBS1	5,731
GJA1	4,942
KARS1	4,681
MCM2	4,472
RDX	3,167
KITLG	3,075
MYO6	2,972
TJP2	2,916
WHRN	2,499
MYO1F	2,418

Intra-cohort edges

A	B	Sources
ACTG1	EPS8L2	biogrid_interaction
ADAMTS1	THBS1	string_interaction
ADGRV1	CDH23	string_interaction
ADGRV1	CIB2	string_interaction
ADGRV1	GRXCR1	string_interaction
ADGRV1	LHFPL5	string_interaction
ADGRV1	MYO15A	string_interaction
ADGRV1	OTOG	string_interaction
ADGRV1	OTOGL	string_interaction
ADGRV1	PCDH15	string_interaction
ADGRV1	TMC1	string_interaction
ADGRV1	USH1G	string_interaction
ADGRV1	WHRN	string_interaction
CABP2	GRXCR1	string_interaction
CABP2	GRXCR2	string_interaction
CABP2	ILDR1	string_interaction
CABP2	OTOG	string_interaction
CABP2	PJVK	string_interaction
CABP2	STRC	string_interaction
CABP2	TMIE	string_interaction
CDH23	CEACAM16	string_interaction
CDH23	CIB2	string_interaction
CDH23	COCH	biogrid_interaction, intact
CDH23	ESPN	string_interaction
CDH23	GJB2	string_interaction
CDH23	GJB3	string_interaction
CDH23	GJB6	string_interaction
CDH23	GRXCR1	string_interaction
CDH23	KCNQ4	string_interaction
CDH23	LHFPL5	string_interaction
CDH23	LOXHD1	string_interaction
CDH23	MYH14	string_interaction
CDH23	MYO15A	string_interaction
CDH23	MYO1F	string_interaction
CDH23	MYO6	string_interaction
CDH23	OTOA	string_interaction
CDH23	OTOG	string_interaction
CDH23	OTOGL	string_interaction
CDH23	PCDH15	string_interaction
CDH23	PJVK	string_interaction
CDH23	SLC26A5	string_interaction
CDH23	STRC	string_interaction
CDH23	TMC1	string_interaction
CDH23	TMIE	string_interaction
CDH23	TMPRSS3	string_interaction
CDH23	USH1C	biogrid_interaction, intact
CDH23	USH1G	string_interaction
CDH23	WHRN	string_interaction
CEACAM16	GRXCR1	string_interaction
CEACAM16	LOXHD1	string_interaction

Structural data

PDB: 43 · AlphaFold-only: 45 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM2	P49736	39
GJB2	P29033	24
TNC	P24821	21
GJA1	P17302	19
P2RX2	Q9UBL9	18
DIABLO	Q9NR28	16
KARS1	Q15046	14
KCNQ4	P56696	13
BDP1	A6H8Y1	13
THBS1	P07996	11
USH1C	Q9Y6N9	11
ACTG1	P63261	10
MYO6	Q9UM54	8
PCDH15	Q96QU1	8
IKZF2	Q9UKS7	7
CDH23	Q9H251	6
KITLG	P21583	6
ROR1	Q01973	5
WHRN	Q9P202	5
SLC26A5	P58743	4
ADAMTS1	Q9UHI8	4
RORA	P35398	3
USH1G	Q495M9	3
MARVELD2	Q8N4S9	3
ESRRB	O95718	3
MYH14	Q7Z406	2
SYNE4	Q8N205	2
RDX	P35241	2
TJP2	Q9UDY2	2
EPS8L2	Q9H6S3	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NARS2	Q96I59	91.59
CLRN2	A0PK11	91.15
CEMIP	Q8WUJ3	90.69
TMTC2	Q8N394	90.57
CEACAM16	Q2WEN9	90.50
MPZL2	O60487	89.54
HOMER2	Q9NSB8	89.20
LHFPL5	Q8TAF8	89.11
TMPRSS3	P57727	87.09
GRAP	Q13588	86.28
GIPC3	Q8TF64	85.45
MYO1A	Q9UBC5	85.11
TBC1D24	Q9ULP9	84.46
OTOA	Q7RTW8	84.12
LOXHD1	Q8IVV2	84.00
SLC44A4	Q53GD3	83.79
GJB6	O95452	82.33
MYO1F	O00160	81.47
CLDN14	O95500	80.00
TMPRSS5	Q9H3S3	79.62
GJB3	O75712	79.29
ADCY1	Q08828	78.34
TECTA	O75443	77.64
ELMOD3	Q96FG2	76.18
GRXCR1	A8MXD5	75.36
CDC14A	Q9UNH5	73.77
OTOGL	Q3ZCN5	72.19
SEZ6	Q53EL9	70.43
STRC	Q7RTU9	69.21
CABP2	Q9NPB3	68.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 322. Enrichment computed across 110 evidence-associated genes (78 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 78 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory processing of sound by outer hair cells of the cochlea	27	70.6×	4e-43	CDH23, RIPOR2, ACTG1, STRC, TMC1, LHFPL5, OTOGL, KCNQ4 (+19 more)
Sensory processing of sound by inner hair cells of the cochlea	26	54.4×	7e-38	CDH23, CABP2, RIPOR2, ACTG1, STRC, TMC1, LHFPL5, KCNQ4 (+18 more)
Sensory processing of sound	10	39.6×	4e-12	CDH23, CABP2, ACTG1, STRC, LHFPL5, KCNQ4, MYO15A, MYO7A (+2 more)
Sensory Perception	10	12.2×	6e-07	CDH23, CABP2, ACTG1, STRC, LHFPL5, KCNQ4, MYO15A, MYO7A (+2 more)
Gap junction degradation	3	36.6×	0.004	ACTG1, MYO6, GJA1
Oligomerization of connexins into connexons	2	97.6×	0.006	GJB2, GJA1
Transport of connexins along the secretory pathway	2	97.6×	0.006	GJB2, GJA1
Gap junction assembly	4	15.0×	0.006	GJB2, GJB6, GJA1, GJB3
Mitochondrial tRNA aminoacylation	3	20.0×	0.015	KARS1, LARS2, NARS2
Release of apoptotic factors from the mitochondria	2	41.8×	0.028	DIABLO, GSDME
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	2	41.8×	0.028	MCM2, MITF
Non-integrin membrane-ECM interactions	4	7.9×	0.043	ACTG1, TNC, COL11A2, COL4A5
Formation of annular gap junctions	2	26.6×	0.058	ACTG1, GJA1
tRNA Aminoacylation	3	11.0×	0.058	KARS1, LARS2, NARS2
RHOBTB GTPase Cycle	2	20.9×	0.085	ACTG1, MYO6
MITF-M-regulated melanocyte development	4	5.9×	0.097	KARS1, MCM2, MET, MITF
Sema4D in semaphorin signaling	2	17.2×	0.111	MYH14, MET
Defective SLC26A4 causes Pendred syndrome (PDS)	1	146.4×	0.122	SLC26A4
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	2	14.6×	0.137	MET, MITF
Transcriptional and post-translational regulation of MITF-M expression and activity	3	6.9×	0.153	KARS1, KITLG, MITF
Gap junction trafficking and regulation	2	12.2×	0.161	ACTG1, MYO6
Gap junction trafficking	2	12.2×	0.161	ACTG1, MYO6
RHOBTB2 GTPase cycle	2	12.2×	0.161	ACTG1, MYO6
R-HSA-2142850	1	73.2×	0.175	CEMIP
Drug-mediated inhibition of MET activation	1	73.2×	0.175	MET
Syndecan interactions	2	10.8×	0.179	TNC, THBS1
Semaphorin interactions	2	10.1×	0.198	MYH14, MET
Regulation of gap junction activity	1	48.8×	0.199	GJA1
MET activates STAT3	1	48.8×	0.199	MET
Regulation of MITF-M dependent genes involved in metabolism	1	48.8×	0.199	MITF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 103 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of sound	54	52.9×	1e-80	TECTA, TMPRSS3, CDH23, CABP2, RIPOR2, OTOA, CCDC50, LHFPL5 (+46 more)
auditory receptor cell stereocilium organization	12	98.2×	5e-20	TECTA, CDH23, STRC, LHFPL5, MYO7A, WHRN, TRIOBP, PDZD7 (+4 more)
sensory perception of light stimulus	8	145.4×	3e-15	CDH23, MYO7A, USH1C, USH2A, PCDH15, USH1G, WHRN, ADGRV1
detection of mechanical stimulus involved in sensory perception of sound	7	63.6×	1e-09	STRC, TMC1, LHFPL5, WHRN, ADGRV1, PDZD7, PJVK
equilibrioception	5	116.9×	2e-08	CDH23, MYO7A, USH1C, PCDH15, USH1G
photoreceptor cell maintenance	8	27.9×	4e-08	CDH23, USH1C, USH2A, PCDH15, USH1G, ADGRV1, CIB2, ESRRB
stereocilium maintenance	4	163.6×	1e-07	ELMOD3, TPRN, PJVK, CLRN2
inner ear receptor cell stereocilium organization	6	49.1×	1e-07	OTOGL, USH1C, USH1G, WHRN, ADGRV1, GRXCR1
inner ear receptor cell differentiation	4	130.9×	4e-07	USH2A, WHRN, ADGRV1, PDZD7
inner ear auditory receptor cell differentiation	5	58.4×	9e-07	MYO6, USH1C, USH2A, GSDME, POU4F3
inner ear morphogenesis	7	20.4×	3e-06	KCNQ4, MYO15A, MYO6, USH1C, USH1G, TMIE, POU4F3
inner ear development	6	21.8×	2e-05	EYA4, GJB6, ROR1, PCDH15, ADGRV1, ESRRB
cochlea development	5	22.7×	1e-04	CDH23, MYO7A, SLC26A5, GRXCR1, MCM2
visual perception	9	7.0×	3e-04	CDH23, CABP2, EYA4, MYO7A, USH2A, WFS1, ADGRV1, MYO3A (+1 more)
actin filament-based movement	4	31.2×	3e-04	MYH14, MYO6, MYO7A, MYO1A
gap junction assembly	3	61.4×	5e-04	GJB2, GJB6, GJA1
auditory receptor cell development	3	54.5×	6e-04	TMC1, ELMOD3, PDZD7
L-arabinose metabolic process	2	163.6×	0.001	OTOGL, OTOG
maintenance of blood-brain barrier	4	18.7×	0.002	ACTG1, GJB6, TJP2, GJA1
establishment of protein localization	4	16.8×	0.003	USH2A, WHRN, ADGRV1, PDZD7
bicellular tight junction assembly	4	12.8×	0.007	CLDN14, CLDN9, MARVELD2, GRHL2
maintenance of animal organ identity	2	65.4×	0.010	USH2A, ADGRV1
establishment of localization in cell	5	7.8×	0.012	ILDR1, USH2A, WHRN, PDZD7, GRXCR1
gap junction-mediated intercellular transport	2	54.5×	0.014	GJB2, GJB6
neuromuscular junction development	3	15.3×	0.023	TNC, P2RX2, COL4A5
microvillus assembly	2	36.4×	0.030	RDX, MYO1A
calcium ion homeostasis	3	12.9×	0.034	WFS1, CIB2, TMTC2
excitatory postsynaptic potential	3	12.9×	0.034	SEZ6, S1PR2, MET
actin filament organization	5	5.8×	0.037	MYO15A, MYO6, MYO7A, MYO1A, MYO1F
nervous system process	2	23.4×	0.060	WFS1, ADGRV1

Therapeutics

Drug target analysis

Approved (phase 4): 9 · Phase ≥3: 10 · Phased (≥1): 11 · Undrugged: 78

Druggability breadth: 34 of 110 evidence-associated genes (31%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MYH14	TUCATINIB
GJB2	KANAMYCIN
KARS1	IMATINIB
KCNQ4	EZOGABINE
RORA	TRETINOIN
P2RX2	GEFAPIXANT
S1PR2	OZANIMOD
ESRRB	ESTRADIOL
GJA1	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
P2RX2	4	4
KCNQ4	2	4
RORA	2	4
ADCY1	2	3
ESRRB	2	4
MYH14	1	4
GJB2	1	4
KARS1	1	4
MSRB3	1	2
S1PR2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TUCATINIB	4	MYH14
KANAMYCIN	4	GJA1, GJB2
IMATINIB	4	KARS1
EZOGABINE	4	KCNQ4
TRETINOIN	4	RORA
GEFAPIXANT	4	P2RX2
OZANIMOD	4	S1PR2
ESTRADIOL	4	ESRRB
FLINDOKALNER	3	KCNQ4
SURAMIN	3	P2RX2
PYRIDOXAL PHOSPHATE ANHYDROUS	3	P2RX2
NB-001	3	ADCY1
ELIAPIXANT	2	P2RX2
COLFORSIN	2	ADCY1
MOLIBRESIB	2	MSRB3
GENISTEIN	2	ESRRB
CINTIRORGON	1	RORA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
S1PR2	147	Functional:78, Binding:69
RORA	115	Binding:111, Functional:3, Unclassified:1
P2RX2	96	Binding:67, Functional:29
KCNQ4	48	Binding:42, Functional:3, ADMET:2, Toxicity:1
ADCY1	47	Binding:34, Functional:12, ADMET:1
KARS1	46	Binding:45, ADMET:1
ROR1	40	Binding:40
ESRRB	27	Binding:19, Functional:8
IKZF2	26	Binding:26
MCM2	22	Binding:22
CDC14A	19	Binding:18, ADMET:1
PCDH15	9	Binding:9
THBS1	8	Binding:8
ADAMTS1	8	Binding:7, Toxicity:1
MSRB3	7	Binding:6, ADMET:1
GJB2	5	Binding:5
GJA1	4	Binding:4
MVD	3	Binding:3
MYH14	1	Binding:1
MYO15A	1	Binding:1
RDX	1	Binding:1
KITLG	1	Binding:1
MYO1F	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KARS1	6.1.1.6	lysine-tRNA ligase
ROR1	2.7.10.1	receptor protein-tyrosine kinase
ADAMTS1	3.4.24.B11, 3.4.24.B12	,
ADCY1	4.6.1.1	adenylate cyclase
NARS2	6.1.1.22	asparagine-tRNA ligase
MSRB3	1.8.4.12, 1.8.4.B3	peptide-methionine (R)-S-oxide reductase,
MVD	4.1.1.33	diphosphomevalonate decarboxylase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RORA	115
S1PR2	147

Pharmacogenomics

Cohort genes with a PharmGKB record: 89; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

17 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TUCATINIB	4	MYH14
KANAMYCIN	4	GJA1, GJB2
IMATINIB	4	KARS1
EZOGABINE	4	KCNQ4
TRETINOIN	4	RORA
GEFAPIXANT	4	P2RX2
OZANIMOD	4	S1PR2
ESTRADIOL	4	ESRRB
FLINDOKALNER	3	KCNQ4
SURAMIN	3	P2RX2
PYRIDOXAL PHOSPHATE ANHYDROUS	3	P2RX2
NB-001	3	ADCY1
ELIAPIXANT	2	P2RX2
COLFORSIN	2	ADCY1
MOLIBRESIB	2	MSRB3
GENISTEIN	2	ESRRB
CINTIRORGON	1	RORA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	9	MYH14, GJB2, KARS1, KCNQ4, RORA, P2RX2, S1PR2, ESRRB, GJA1
B	Phased (≥1) drug, not yet approved	2	ADCY1, MSRB3
C	Druggable family + PDB, no drug	5	TNC, SLC26A5, ROR1, ADAMTS1, MVD
D	Druggable family + AlphaFold only, no drug	9	TMPRSS3, ILDR1, CEACAM16, TMPRSS5, SEZ6, CDC14A, ADGRV1, NARS2, MPZL2
E	Difficult family or no structure, no drug	64	TECTA, CDH23, CABP2, RIPOR2, SLC44A4, ACTG1, STRC, OTOA, TMC1, CCDC50 (+54 more)

Undrugged target profiles

78 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GJB6	0	GJB2, GJA1
MYO15A	1	GJB2
POU3F4	0	GJB2
ESPN	0	GJB2
TMIE	0	GJB2
GJB3	0	KCNQ4, GJB2
TECTA	0	—
TMPRSS3	0	—
CDH23	0	—
CABP2	0	—
RIPOR2	0	—
SLC44A4	0	—
ACTG1	0	—
STRC	0	—
OTOA	0	—
TMC1	0	—
CCDC50	0	—
GIPC3	0	—
LHFPL5	0	—
COCH	0	—
LOXHD1	0	—
SYNE4	0	—
OTOGL	0	—
ILDR1	0	—
DMXL2	0	—
CEACAM16	0	—
EYA4	0	—
TNC	0	—
MYO6	0	—
MYO7A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations