Hearing loss disorder

Summary

Hearing loss disorder (MONDO:0005365) is a disease (an umbrella term covering 11 Mondo subtypes) caused by variants in GJB2 and PNPT1, with 75 cohort genes (299 GWAS associations across 70 studies) and 602 clinical trials. The dominant Reactome pathway is Sensory processing of sound by outer hair cells of the cochlea (27 cohort genes). Top therapeutic interventions include ginkgo, dextrose, and fibrinogen i 125.

At a glance

• Causal genes: GJB2 (GenCC Definitive), PNPT1 (GenCC Definitive)
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 299
• ClinVar variants: 581
• Clinical trials: 602

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hearing loss disorder
Mondo ID	MONDO:0005365
EFO	EFO:0004238
MeSH	D034381
ICD-10-CM	H90
NCIT	C35731
SNOMED CT	15188001
UMLS	C1384666
MedGen	235586
Is cancer (heuristic)	no

Also known as: deafness · hearing impairment · hearing loss · hypoacuses · hypoacusis · loss of hearing · loss, hearing

Data availability: 581 ClinVar variants · 1 ClinGen variant curation · 299 GWAS associations (70 studies) · 12 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 11 Mondo subtypes.

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

Related subtypes (3): cortical deafness, hyperacusis, tinnitus

Subtypes (11): Johanson-Blizzard syndrome, noise induced hearing loss, nonsyndromic genetic 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

Genetics & variants

GWAS landscape

299 GWAS associations across 70 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
chr15:89236386	2e-40		T	0.07
rs36062310	3e-32	KLHDC7B	A	1.15
chr15:89232249	3e-30		C	0.08
chr14:52514912	2e-28		T	0.05
rs12594617	6e-28	ISG20 - ACAN	C	0.08
rs6496519	2e-27	ISG20 - ACAN	C	0.06
chr6:133794511	8e-27		G	0.05
rs528708560	1e-25	PLEKHG4B	?
rs6871548	2e-25	ARHGEF28	T	1.05
rs190199516	6e-24	PDCD6-AHRR, AHRR	C	0.84
rs2254303	1e-23	CRIP3, ZNF318	A	1.05
rs10901863	6e-23	CTBP2	T	1.05
rs11738813	1e-22	ARHGEF28	?	0.06
rs537688122	1e-21	PDCD6-AHRR, PDCD6-DT, PDCD6	G	1.35
rs571370281	1e-21	PDCD6-AHRR, PDCD6-DT, PDCD6	G	1.31
chr1:168828980	1e-21		T	0.05
rs4399218	2e-21	LINC01681	T	0.04
chr1:103549633	3e-21		C	0.04
rs9373056	5e-21	EYA4	C	0.05
chr18:42292338	6e-20		T	0.05
rs34929759	9e-20	ARHGEF28	?
rs1806319	5e-19	TYR - NOX4	?
rs549592074	5e-19	PDCD6-DT, PDCD6, PDCD6-AHRR	C	1.37
rs739138	5e-19	TRIOBP	A	0.95
chr2:54862003	1e-18		G	0.04
rs200566	1e-18	LINC00970, LINC00970	A	0.05
rs553448379	3e-18	ZNF318	?
rs67307131	3e-18	PHLDB1	T	0.96
rs9493627	5e-18	EYA4	G	0.05
rs7451690	6e-18	RREB1	C	0.04

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475909	Verma A	2024	229,580	176,720	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90042882	Jiang L	2021	114,318	323,449	A generalized linear mixed model association tool for biobank-scale data.
GCST90475385	Verma A	2024	106,155	209,513	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90081539	Backman JD	2021	98,675	196,355	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90085525	Backman JD	2021	98,675	196,355	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90245779	Cornejo-Sanchez DM	2023	95,794	141,007	Rare-variant association analysis reveals known and new age-related hearing loss genes.
GCST90044775	Liu W	2021	91,080	257,037	A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens.
GCST90245775	Cornejo-Sanchez DM	2023	65,660	96,601	Rare-variant association analysis reveals known and new age-related hearing loss genes.
GCST90245778	Cornejo-Sanchez DM	2023	64,953	141,007	Rare-variant association analysis reveals known and new age-related hearing loss genes.
GCST90245780	Cornejo-Sanchez DM	2023	54,853	141,007	Rare-variant association analysis reveals known and new age-related hearing loss genes.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	7
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	41

MAF distribution

Bucket	Variants
common (>=0.05)	43
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	7

Functional consequences

Consequence	Count
intron_variant	24
unknown	8
intergenic_variant	8
missense_variant	7
synonymous_variant	1
regulatory_region_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr15:89236386				0.194			2e-40	Tier 4: intronic/intergenic
rs36062310	22	50549676	G>A,C,T	0.05	missense_variant	KLHDC7B	3e-32	Tier 1: coding
chr15:89232249				0.197			3e-30	Tier 4: intronic/intergenic
chr14:52514912				0.417			2e-28	Tier 4: intronic/intergenic
rs12594617	15	88715387	C>A,G,T	0.179	intergenic_variant	ISG20 - ACAN	6e-28	Tier 4: intronic/intergenic
rs6496519	15	88694953	C>T	0.177	intergenic_variant	ISG20 - ACAN	2e-27	Tier 4: intronic/intergenic
chr6:133794511				0.314			8e-27	Tier 4: intronic/intergenic
rs528708560	5	132752	A>T		intron_variant	PLEKHG4B	1e-25	Tier 4: intronic/intergenic
rs6871548	5	73780199	C>G,T	0.05	intron_variant	ARHGEF28	2e-25	Tier 4: intronic/intergenic
rs190199516	5	329201	T>C		intron_variant	PDCD6-AHRR, AHRR	6e-24	Tier 4: intronic/intergenic
rs2254303	6	43308652	G>A,C	0.05	intron_variant	CRIP3, ZNF318	1e-23	Tier 4: intronic/intergenic
rs10901863	10	125123701	C>T	0.05	intron_variant	CTBP2	6e-23	Tier 4: intronic/intergenic
rs11738813	5	73792077	T>A,C,G	0.05	intron_variant	ARHGEF28	1e-22	Tier 4: intronic/intergenic
rs537688122	5	272741	A>C,G		synonymous_variant	PDCD6-AHRR, PDCD6-DT, PDCD6	1e-21	Tier 4: intronic/intergenic
rs571370281	5	272755	A>G		missense_variant	PDCD6-AHRR, PDCD6-DT, PDCD6	1e-21	Tier 1: coding
chr1:168828980				0.333			1e-21	Tier 4: intronic/intergenic
rs4399218	1	170226090	T>G	0.327	intron_variant	LINC01681	2e-21	Tier 4: intronic/intergenic
chr1:103549633				0.413			3e-21	Tier 4: intronic/intergenic
rs9373056	6	133476070	C>T	0.313	intron_variant	EYA4	5e-21	Tier 4: intronic/intergenic
chr18:42292338				0.16			6e-20	Tier 4: intronic/intergenic
rs34929759	5	73777250	T>C	0.05	intron_variant	ARHGEF28	9e-20	Tier 4: intronic/intergenic
rs1806319	11	89304768	T>A,C	0.05	intergenic_variant	TYR - NOX4	5e-19	Tier 4: intronic/intergenic
rs549592074	5	272748	G>A,C		missense_variant	PDCD6-DT, PDCD6, PDCD6-AHRR	5e-19	Tier 1: coding
rs739138	22	37726455	A>G,T	0.05	missense_variant	TRIOBP	5e-19	Tier 1: coding
chr2:54862003				0.484			1e-18	Tier 4: intronic/intergenic
rs200566	1	168855287	A>C,G,T	0.407	intron_variant	LINC00970, LINC00970	1e-18	Tier 4: intronic/intergenic
rs553448379	6	43320916	AAAT>A		intergenic_variant	ZNF318	3e-18	Tier 4: intronic/intergenic
rs67307131	11	118609508	T>A,C	0.05	intron_variant	PHLDB1	3e-18	Tier 4: intronic/intergenic
rs9493627	6	133468590	G>A,C	0.352	missense_variant	EYA4	5e-18	Tier 1: coding
rs7451690	6	7109200	C>T	0.478	intron_variant	RREB1	6e-18	Tier 4: intronic/intergenic

ClinVar germline variants

581 retrieved; paginated sample, class counts are floors:

298 uncertain significance, 119 conflicting classifications of pathogenicity, 55 pathogenic/likely pathogenic, 46 likely pathogenic, 46 pathogenic, 9 likely benign, 4 benign/likely benign, 4 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267815	46;X;t(X;5)(p11.23;q35)dn		Pathogenic	criteria provided, single submitter
18322	NM_001614.5(ACTG1):c.721G>A (p.Glu241Lys)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064951	NM_032119.4(ADGRV1):c.1477C>T (p.Arg493Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374506	NM_001378454.1(ALMS1):c.1732del (p.Arg578fs)	ALMS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52603	NM_000059.4(BRCA2):c.8487+3A>G	BRCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4389	NM_057176.3(BSND):c.10G>T (p.Glu4Ter)	BSND	Pathogenic	criteria provided, multiple submitters, no conflicts
1703679	GRCh37/hg19 15q24.1-24.2(chr15:74398068-76054094)	CCDC33	Pathogenic	no assertion criteria provided
978271	NM_022124.6(CDH23):c.2334G>A (p.Trp778Ter)	CDH23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523238	GRCh37/hg19 17p12(chr17:14215739-15422582)	CDRT4	Pathogenic	criteria provided, single submitter
523521	NM_017780.4(CHD7):c.1513C>T (p.Gln505Ter)	CHD7	Pathogenic	criteria provided, single submitter
1064924	NM_006383.4(CIB2):c.196C>T (p.Arg66Trp)	CIB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064997	NM_001146079.2(CLDN14):c.89G>A (p.Trp30Ter)	CLDN14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189331	NM_001146079.2(CLDN14):c.242G>A (p.Arg81His)	CLDN14-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4851	NM_001146079.2(CLDN14):c.254T>A (p.Val85Asp)	CLDN14-AS1	Pathogenic	criteria provided, single submitter
4392	NM_052995.2(CLRN1):c.300T>G (p.Tyr100Ter)	CLRN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065111	NM_004086.3(COCH):c.538C>T (p.Arg180Ter)	COCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6611	NM_004086.3(COCH):c.151C>T (p.Pro51Ser)	COCH	Pathogenic	reviewed by expert panel
24757	NM_033380.3(COL4A5):c.4706G>A (p.Arg1569Gln)	COL4A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
402130	NM_138615.3(DHX30):c.1685A>G (p.His562Arg)	DHX30	Pathogenic	criteria provided, single submitter
493417	NM_005219.5(DIAPH1):c.3268dup (p.Met1090fs)	DIAPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1472670	NM_001012426.2(FOXP4):c.1540G>A (p.Ala514Thr)	FOXP4	Pathogenic	criteria provided, multiple submitters, no conflicts
158605	NM_004004.6(GJB2):c.132G>A (p.Trp44Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
158606	NM_004004.6(GJB2):c.158G>A (p.Cys53Tyr)	GJB2	Pathogenic	criteria provided, single submitter
158607	NM_004004.6(GJB2):c.298C>T (p.His100Tyr)	GJB2	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
158609	NM_004004.6(GJB2):c.647_650del (p.Arg216fs)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 70 · Orphanet: 121 · 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
GJB2	Definitive	Autosomal dominant	hearing loss disorder	26
KCNQ4	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 2A	6
PNPT1	Definitive	Autosomal recessive	hearing loss disorder	10
IKZF2	Strong	Autosomal dominant	nonsyndromic genetic hearing loss	6
FMN1	Moderate	Autosomal recessive	hearing loss disorder
GAS2	Moderate	Autosomal recessive	hearing loss, autosomal recessive 125	3
SPATC1L	Moderate	Autosomal recessive	hearing loss disorder	2
THOC1	Moderate	Autosomal dominant	hearing loss disorder	2
FOXI1	Limited	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 4	7
POLD3	Limited	Autosomal dominant	hearing loss disorder	2
SIK3	Limited	Autosomal dominant	hearing loss disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXI1	Orphanet:402041	Autosomal recessive distal renal tubular acidosis
FOXI1	Orphanet:705	Pendred syndrome
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
KCNQ4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
IKZF2	Orphanet:697389	Combined immunodeficiency due to HELIOS deficiency
IKZF2	Orphanet:699599	ICHAD syndrome
PNPT1	Orphanet:101111	Spinocerebellar ataxia type 25
PNPT1	Orphanet:319514	Combined oxidative phosphorylation defect type 13
PNPT1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SALL1	Orphanet:857	Townes-Brocks syndrome
BMP2	Orphanet:261295	20p12.3 microdeletion syndrome
BMP2	Orphanet:93396	Brachydactyly type A2
SIX1	Orphanet:107	BOR syndrome
SIX1	Orphanet:52429	Branchiootic syndrome
SIX1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
SMPX	Orphanet:700163	SMPX-related distal myopathy
SMPX	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
TCOF1	Orphanet:861	Treacher-Collins syndrome
TJP2	Orphanet:238475	Familial hypercholanemia
TJP2	Orphanet:480483	Progressive familial intrahepatic cholestasis type 4
TJP2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TMPRSS3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
TYR	Orphanet:352734	Minimal pigment oculocutaneous albinism type 1
TYR	Orphanet:352737	Temperature-sensitive oculocutaneous albinism type 1
TYR	Orphanet:79431	Oculocutaneous albinism type 1A
TYR	Orphanet:79434	Oculocutaneous albinism type 1B
TYR	Orphanet:895	Waardenburg syndrome type 2
USH1C	Orphanet:231169	Usher syndrome type 1

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXI1	HGNC:3815	ENSG00000168269	Q12951	Forkhead box protein I1	gencc,clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	gencc,clinvar
KCNQ4	HGNC:6298	ENSG00000117013	P56696	Potassium voltage-gated channel subfamily KQT member 4	gencc,clinvar
SPATC1L	HGNC:1298	ENSG00000160284	Q9H0A9	Speriolin-like protein	gencc
IKZF2	HGNC:13177	ENSG00000030419	Q9UKS7	Zinc finger protein Helios	gencc
THOC1	HGNC:19070	ENSG00000079134	Q96FV9	THO complex subunit 1	gencc
POLD3	HGNC:20932	ENSG00000077514	Q15054	DNA polymerase delta subunit 3	gencc
PNPT1	HGNC:23166	ENSG00000138035	Q8TCS8	Polyribonucleotide nucleotidyltransferase 1, mitochondrial	gencc
SIK3	HGNC:29165	ENSG00000160584	Q9Y2K2	Serine/threonine-protein kinase SIK3	gencc
FMN1	HGNC:3768	ENSG00000248905	Q68DA7	Formin-1	gencc
GAS2	HGNC:4167	ENSG00000148935	O43903	Growth arrest-specific protein 2	gencc
SALL1	HGNC:10524	ENSG00000103449	Q9NSC2	Sal-like protein 1	clinvar
BMP2	HGNC:1069	ENSG00000125845	P12643	Bone morphogenetic protein 2	clinvar
SEMA3F	HGNC:10728	ENSG00000001617	Q13275	Semaphorin-3F	clinvar
SIX1	HGNC:10887	ENSG00000126778	Q15475	Homeobox protein SIX1	clinvar
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
SMPX	HGNC:11122	ENSG00000091482	Q9UHP9	Small muscular protein	clinvar
TCOF1	HGNC:11654	ENSG00000070814	Q13428	Treacle protein	clinvar
THBS1	HGNC:11785	ENSG00000137801	P07996	Thrombospondin-1	clinvar
TJP2	HGNC:11828	ENSG00000119139	Q9UDY2	Tight junction protein 2	clinvar
TMPRSS3	HGNC:11877	ENSG00000160183	P57727	Transmembrane protease serine 3	clinvar
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	clinvar
USH1C	HGNC:12597	ENSG00000006611	Q9Y6N9	Harmonin	clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar
CLRN1	HGNC:12605	ENSG00000163646	P58418	Clarin-1	clinvar
VAV1	HGNC:12657	ENSG00000141968	P15498	Proto-oncogene vav	clinvar
TSPEAR	HGNC:1268	ENSG00000175894	Q8WU66	Thrombospondin-type laminin G domain and EAR repeat-containing protein	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
NSDHL	HGNC:13398	ENSG00000147383	Q15738	Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating	clinvar
CLIC5	HGNC:13517	ENSG00000112782	Q9NZA1	Chloride intracellular channel protein 5	clinvar
BDP1	HGNC:13652	ENSG00000145734	A6H8Y1	Transcription factor TFIIIB component B’’ homolog	clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	clinvar
CABP2	HGNC:1385	ENSG00000167791	Q9NPB3	Calcium-binding protein 2	clinvar
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	clinvar
CIC	HGNC:14214	ENSG00000079432	Q96RK0	Protein capicua homolog	clinvar
CDRT4	HGNC:14383	ENSG00000239704	Q8N9R6	CMT1A duplicated region transcript 4 protein	clinvar
ACTG1	HGNC:144	ENSG00000184009	P63261	Actin, cytoplasmic 2	clinvar
PCDH15	HGNC:14674	ENSG00000150275	Q96QU1	Protocadherin-15	clinvar
SHANK1	HGNC:15474	ENSG00000161681	Q9Y566	SH3 and multiple ankyrin repeat domains protein 1	clinvar
DIAPH3	HGNC:15480	ENSG00000139734	Q9NSV4	Protein diaphanous homolog 3	clinvar
B3GNT4	HGNC:15683	ENSG00000176383	Q9C0J1	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 4	clinvar
OXR1	HGNC:15822	ENSG00000164830	Q8N573	Oxidation resistance protein 1	clinvar
ABHD12	HGNC:15868	ENSG00000100997	Q8N2K0	Lysophosphatidylserine lipase ABHD12	clinvar
NAV3	HGNC:15998	ENSG00000067798	Q8IVL0	Neuron navigator 3	clinvar
STRC	HGNC:16035	ENSG00000242866	Q7RTU9	Stereocilin	clinvar
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	clinvar
USH1G	HGNC:16356	ENSG00000182040	Q495M9	pre-mRNA splicing regulator USH1G	clinvar
WHRN	HGNC:16361	ENSG00000095397	Q9P202	Whirlin	clinvar
OTOA	HGNC:16378	ENSG00000155719	Q7RTW8	Otoancorin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXI1	Forkhead box protein I1	Transcriptional activator required for the development of normal hearing, sense of balance and kidney function.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
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.
IKZF2	Zinc finger protein Helios	Transcription factor, which stabilizes the noninflammatory phenotype of regulatory T cells (Tregs).
THOC1	THO complex subunit 1	Component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA.
POLD3	DNA polymerase delta subunit 3	Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex.
PNPT1	Polyribonucleotide nucleotidyltransferase 1, mitochondrial	RNA-binding protein implicated in numerous RNA metabolic processes.
SIK3	Serine/threonine-protein kinase SIK3	Positive regulator of mTOR signaling that functions by triggering the degradation of DEPTOR, an mTOR inhibitor.
FMN1	Formin-1	Plays a role in the formation of adherens junction and the polymerization of linear actin cables.
GAS2	Growth arrest-specific protein 2	Required to maintain microtubule bundles in inner ear supporting cells, affording them with mechanical stiffness to transmit sound energy through the cochlea.
SALL1	Sal-like protein 1	Transcriptional repressor involved in organogenesis.
BMP2	Bone morphogenetic protein 2	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis.
SEMA3F	Semaphorin-3F	May play a role in cell motility and cell adhesion.
SIX1	Homeobox protein SIX1	Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
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.
TCOF1	Treacle protein	Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification.
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.
TMPRSS3	Transmembrane protease serine 3	Probable serine protease that plays a role in hearing.
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
TYR	Tyrosinase	This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds.
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.
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.
CLRN1	Clarin-1	May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.
VAV1	Proto-oncogene vav	Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.
TSPEAR	Thrombospondin-type laminin G domain and EAR repeat-containing protein	Plays a critical role in tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
NSDHL	Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating	Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis.
CLIC5	Chloride intracellular channel protein 5	In the soluble state, catalyzes glutaredoxin-like thiol disulfide exchange reactions with reduced glutathione as electron donor.
BDP1	Transcription factor TFIIIB component B’’ homolog	General activator of RNA polymerase III transcription.
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.
CACNA1D	Voltage-dependent L-type calcium channel subunit alpha-1D	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CIC	Protein capicua homolog	Transcriptional repressor which plays a role in development of the central nervous system (CNS).
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.
PCDH15	Protocadherin-15	Calcium-dependent cell-adhesion protein.
SHANK1	SH3 and multiple ankyrin repeat domains protein 1	Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and H…
DIAPH3	Protein diaphanous homolog 3	Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.
B3GNT4	N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 4	Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine.
OXR1	Oxidation resistance protein 1	May be involved in protection from oxidative damage.
ABHD12	Lysophosphatidylserine lipase ABHD12	Lysophosphatidylserine (LPS) lipase that mediates the hydrolysis of lysophosphatidylserine, a class of signaling lipids that regulates immunological and neurological processes.
NAV3	Neuron navigator 3	Is involved in microtubule cytoskeleton organization and plays a role in cell migration.
STRC	Stereocilin	Essential to the formation of horizontal top connectors between outer hair cell stereocilia.
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).
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.
OTOA	Otoancorin	May act as an adhesion molecule.
NLRP3	NACHT, LRR and PYD domains-containing protein 3	Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis.
BSND	Barttin	Regulatory subunit of anion-selective CLCNKA:BSND and CLCNKB:BSND heteromeric channels involved in basolateral chloride conductance along the nephron to achieve urine concentration and maintain systemic acid-base homeostasis, and in the st…

Protein-family classification

Druggable: 14 · Difficult: 17 · Unknown: 44 · Druggable fraction: 0.19

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
Ion channel	4	6.0×	0.042
Scaffold/PPI	9	2.1×	0.129
Kinase	3	1.1×	0.960
Other/Unknown	44	1.1×	0.960
Transcription factor	8	0.9×	0.960
Antibody/Immunoglobulin	2	0.8×	0.960
Protease	1	0.5×	0.960
Enzyme (other)	3	0.5×	0.960
GPCR	1	0.3×	0.960

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXI1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N
KCNQ4	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCNQ_C
SPATC1L	Other/Unknown	no		SPATC1, Speriolin_C, Speriolin_N
IKZF2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF
THOC1	Other/Unknown	no		Death_dom, DEATH-like_dom_sf, THO_THOC1
POLD3	Other/Unknown	no		POLD3, POLD3_sf
PNPT1	Scaffold/PPI	no	2.7.7.8	ExoRNase_PH_dom1, S1_domain, KH_dom
SIK3	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
FMN1	Other/Unknown	no		Formin_Cappuccino_subfam, FH2_Formin, FH2_Formin_sf
GAS2	Other/Unknown	no		CH_dom, GAR_dom, GAR_dom_sf
SALL1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
BMP2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
SEMA3F	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub2, Ig_sub
SIX1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
SMPX	Other/Unknown	no		Chisel
TCOF1	Other/Unknown	no		Treacle_dom, LisH, Treacle
THBS1	Other/Unknown	no		EGF, TSP1_rpt, VWF_dom
TJP2	Scaffold/PPI	no		SH3_domain, PDZ, ZO
TMPRSS3	Protease	yes		SRCR, Trypsin_dom, Peptidase_S1A
TSC1	Other/Unknown	no		Hamartin
TYR	Enzyme (other)	yes	1.14.18.1	Tyrosinase_Cu-bd, Di-copper_centre_dom_sf, Tyrosinase/Hemocyanin
USH1C	Scaffold/PPI	no		PDZ, Harmonin_N, PDZ_sf
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom
CLRN1	Other/Unknown	no		Clarin
VAV1	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
TSPEAR	Other/Unknown	no		EPTP, EAR, ConA-like_dom_sf
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
NSDHL	Enzyme (other)	yes	1.1.1.170	3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, Lipid_A_modif_metabolic_enz
CLIC5	Other/Unknown	no		CLIC, Glutathione-S-Trfase_C-like, Thioredoxin-like_sf
BDP1	Transcription factor	no		SANT/Myb, Homeodomain-like_sf, TFIIIB_B’’_Myb
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
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu
CIC	Other/Unknown	no		HMG_box_dom, Cic_dom, HMG_box_dom_sf
CDRT4	Other/Unknown	no		CDRT4
ACTG1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
PCDH15	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
SHANK1	Scaffold/PPI	no		SH3_domain, PDZ, SAM
DIAPH3	Other/Unknown	no		FH3_dom, GTPase-bd, ARM-like
B3GNT4	Other/Unknown	no		Glyco_trans_31
OXR1	Other/Unknown	no		TLDc_dom, LysM, LysM_dom_sf
ABHD12	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
NAV3	Other/Unknown	no		CH_dom, AAA+_ATPase, ATPase_AAA_core
STRC	Other/Unknown	no		Stereocilin-rel, Stereocilin_LRR
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
USH1G	Scaffold/PPI	no		SAM, Ankyrin_rpt, SAM/pointed_sf
WHRN	Scaffold/PPI	no		PDZ, Whirlin_HN-like_dom2, PDZ_sf
OTOA	Other/Unknown	no		Stereocilin-rel

Expression context

Cohort genes with no expression data: 0.

64 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)	1
broad (>20)	74
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	11
secondary oocyte	7
right hemisphere of cerebellum	7
cerebellar cortex	6
cerebellar hemisphere	6
ventricular zone	6
primordial germ cell in gonad	5
pigmented layer of retina	4
calcaneal tendon	4
sural nerve	4
cervix squamous epithelium	4
right uterine tube	4
adrenal tissue	4
right adrenal gland	4
right adrenal gland cortex	4
metanephros cortex	3
left testis	3
lower esophagus mucosa	3
skeletal muscle tissue of biceps brachii	3
buccal mucosa cell	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXI1	46	tissue_specific	marker	metanephros cortex, adult mammalian kidney, olfactory segment of nasal mucosa
GJB2	196	broad	marker	gingival epithelium, gingiva, penis
KCNQ4	182	broad	marker	pigmented layer of retina, lower esophagus muscularis layer, lower esophagus
SPATC1L	136	ubiquitous	yes	right testis, left testis, testis
IKZF2	232	ubiquitous	marker	thymus, palpebral conjunctiva, amniotic fluid
THOC1	293	ubiquitous	marker	calcaneal tendon, cerebellar hemisphere, cerebellar cortex
POLD3	276	ubiquitous	marker	secondary oocyte, ventricular zone, male germ line stem cell (sensu Vertebrata) in testis
PNPT1	258	ubiquitous	marker	left ventricle myocardium, secondary oocyte, tibialis anterior
SIK3	290	ubiquitous	marker	lateral globus pallidus, corpus callosum, lateral nuclear group of thalamus
FMN1	171	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, primordial germ cell in gonad
GAS2	226	broad	marker	trigeminal ganglion, liver, sural nerve
SALL1	195	broad	marker	ventricular zone, inferior vagus X ganglion, renal medulla
BMP2	238	broad	marker	cartilage tissue, pancreatic ductal cell, pigmented layer of retina
SEMA3F	289	ubiquitous	marker	cervix squamous epithelium, gingival epithelium, lower esophagus mucosa
SIX1	188	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, parotid gland
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
SMPX	186	broad	marker	heart right ventricle, biceps brachii, skeletal muscle tissue of biceps brachii
TCOF1	265	ubiquitous	marker	sural nerve, oocyte, dorsal motor nucleus of vagus nerve
THBS1	271	ubiquitous	marker	stromal cell of endometrium, mucosa of stomach, pericardium
TJP2	134	ubiquitous	marker	corpus callosum, descending thoracic aorta, thoracic aorta
TMPRSS3	177	tissue_specific	marker	pancreatic ductal cell, right uterine tube, bronchial epithelial cell
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
TYR	59	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, upper leg skin
USH1C	203	broad	marker	mucosa of transverse colon, C1 segment of cervical spinal cord, rectum
USH2A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, buccal mucosa cell
CLRN1	61	tissue_specific	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
VAV1	188	broad	marker	granulocyte, monocyte, leukocyte
TSPEAR	88	tissue_specific	yes	primordial germ cell in gonad, adenohypophysis, pituitary gland
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
NSDHL	271	ubiquitous	marker	cervix squamous epithelium, adrenal tissue, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 107.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
THBS1	5,731
POLR1C	5,495
TSC1	5,445
BRCA2	4,839
CHD7	4,819
DHX30	4,364
NLRP3	3,797
PNPT1	3,741
TYR	3,663
SHANK1	3,605

Intra-cohort edges

A	B	Sources
ADGRV1	CDH23	string_interaction
ADGRV1	CLIC5	string_interaction
ADGRV1	CLIC6	string_interaction
ADGRV1	CLRN1	string_interaction
ADGRV1	LHFPL5	string_interaction
ADGRV1	PCDH15	string_interaction
ADGRV1	TMC1	string_interaction
ADGRV1	USH1G	string_interaction
ADGRV1	USH2A	string_interaction
ADGRV1	WHRN	string_interaction
BDP1	POLR1C	intact
BDP1	POLR1D	intact
C10orf105	CDH23	string_interaction
CABP2	CACNA1D	string_interaction
CABP2	STRC	string_interaction
CACNA1D	SHANK1	intact
CACNA1D	WHRN	intact
CATSPER2	STRC	string_interaction
CDH23	CLIC5	string_interaction
CDH23	CLIC6	string_interaction
CDH23	CLRN1	string_interaction
CDH23	GJB2	string_interaction
CDH23	KCNQ4	string_interaction
CDH23	LHFPL5	string_interaction
CDH23	OTOA	string_interaction
CDH23	PCDH15	string_interaction
CDH23	STRC	string_interaction
CDH23	TMC1	string_interaction
CDH23	TMPRSS3	string_interaction
CDH23	TRIOBP	string_interaction
CDH23	USH1C	biogrid_interaction, intact
CDH23	USH1G	string_interaction
CDH23	USH2A	string_interaction
CDH23	WHRN	string_interaction
CLDN14	CLDN9	string_interaction
CLDN14	GJB2	string_interaction
CLDN14	STRC	string_interaction
CLDN14	TJP2	intact, string_interaction
CLDN14	TMC1	string_interaction
CLDN14	TMPRSS3	string_interaction
CLDN14	WHRN	intact
CLDN9	TJP2	string_interaction
CLIC5	CLIC6	biogrid_interaction, intact
CLIC5	KCNQ4	string_interaction
CLIC5	PCDH15	string_interaction
CLIC5	TMC1	string_interaction
CLIC5	USH2A	string_interaction
CLIC6	OXR1	biogrid_interaction, intact
CLIC6	PCDH15	string_interaction
CLIC6	TMC1	string_interaction

Structural data

PDB: 40 · AlphaFold-only: 35 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR1C	O15160	36
POLR1D	P0DPB5	36
GJB2	P29033	24
NLRP3	Q96P20	24
BMP2	P12643	21
BRCA2	P51587	14
KCNQ4	P56696	13
BDP1	A6H8Y1	13
PNPT1	Q8TCS8	11
THBS1	P07996	11
USH1C	Q9Y6N9	11
VAV1	P15498	10
ACTG1	P63261	10
POLD3	Q15054	9
PCDH15	Q96QU1	8
IKZF2	Q9UKS7	7
CIC	Q96RK0	7
SHANK1	Q9Y566	7
CDH23	Q9H251	6
CACNA1D	Q01668	6
KCNT1	Q5JUK3	6
THOC1	Q96FV9	5
SIK3	Q9Y2K2	5
TSC1	Q92574	5
WHRN	Q9P202	5
RBFOX1	Q9NWB1	4
CLIC5	Q9NZA1	3
USH1G	Q495M9	3
POGZ	Q7Z3K3	3
CHD7	Q9P2D1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLRN1	P58418	90.74
LHFPL5	Q8TAF8	89.11
B3GNT4	Q9C0J1	87.51
TSPEAR	Q8WU66	87.47
TMPRSS3	P57727	87.09
CDK20	Q8IZL9	86.08
ABHD12	Q8N2K0	85.60
GIPC3	Q8TF64	85.45
CHSY1	Q86X52	84.20
OTOA	Q7RTW8	84.12
SEMA3F	Q13275	84.06
GAS2	O43903	80.86
CLDN14	O95500	80.00
WFS1	O76024	73.85
CATSPER2	Q96P56	69.83
PNPLA6	Q8IY17	69.75
SPATC1L	Q9H0A9	69.31
STRC	Q7RTU9	69.21
CABP2	Q9NPB3	68.93
SMPX	Q9UHP9	67.55
CDRT4	Q8N9R6	66.42
DMBX1	Q8NFW5	63.71
C10orf105	Q8TEF2	63.46
OXR1	Q8N573	60.31
CLIC6	Q96NY7	60.24
FOXI1	Q12951	60.03
FMN1	Q68DA7	55.95
BSND	Q8WZ55	53.80
SALL1	Q9NSC2	49.54
ALPK3	Q96L96	49.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 621. Enrichment computed across 180 evidence-associated genes (124 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 124 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	44.4×	2e-36	KCNQ4, USH1C, CLIC5, CDH23, ACTG1, PCDH15, STRC, USH1G (+19 more)
Sensory processing of sound by inner hair cells of the cochlea	27	35.5×	2e-33	KCNQ4, USH1C, CLIC5, CDH23, CABP2, CACNA1D, ACTG1, PCDH15 (+19 more)
Sensory processing of sound	12	29.9×	5e-13	KCNQ4, CDH23, CABP2, CACNA1D, ACTG1, STRC, LHFPL5, MYH9 (+4 more)
Sensory Perception	13	10.0×	8e-08	KCNQ4, CDH23, CABP2, CACNA1D, ACTG1, STRC, LHFPL5, LRP2 (+5 more)
Collagen chain trimerization	9	18.8×	1e-07	COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1 (+1 more)
Assembly of collagen fibrils and other multimeric structures	9	14.5×	9e-07	COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1 (+1 more)
Collagen degradation	9	12.8×	3e-06	COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1 (+1 more)
Collagen biosynthesis and modifying enzymes	9	12.4×	3e-06	COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1 (+1 more)
Non-integrin membrane-ECM interactions	9	11.2×	7e-06	ACTG1, COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6 (+1 more)
ECM proteoglycans	9	10.9×	8e-06	COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A3, TNC (+1 more)
Integrin cell surface interactions	9	9.8×	2e-05	THBS1, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A3 (+1 more)
Signaling by PDGF	7	14.3×	3e-05	THBS1, COL2A1, COL4A3, COL4A4, COL4A5, COL9A1, COL9A3
NCAM1 interactions	7	14.0×	3e-05	CACNA1D, COL2A1, COL4A3, COL4A4, COL4A5, COL9A1, COL9A3
Fibronectin matrix formation	5	23.0×	8e-05	COL2A1, COL4A3, COL4A4, COL4A5, COL4A6
Anchoring fibril formation	4	24.6×	7e-04	COL4A3, COL4A4, COL4A5, COL4A6
Crosslinking of collagen fibrils	4	18.4×	0.002	COL4A3, COL4A4, COL4A5, COL4A6
Attachment of bacteria to epithelial cells	4	16.0×	0.004	COL4A3, COL4A4, COL4A5, COL4A6
RNA Polymerase III Transcription Initiation From Type 2 Promoter	4	13.6×	0.007	BDP1, POLR1C, POLR1D, POLR2F
RNA Polymerase III Transcription Initiation From Type 1 Promoter	4	13.2×	0.007	BDP1, POLR1C, POLR1D, POLR2F
RNA Polymerase III Transcription Initiation From Type 3 Promoter	4	13.2×	0.007	BDP1, POLR1C, POLR1D, POLR2F
Laminin interactions	4	12.3×	0.008	COL4A3, COL4A4, COL4A5, COL4A6
MET activates PTK2 signaling	4	12.3×	0.008	COL11A1, COL11A2, COL2A1, HGF
RNA Polymerase III Transcription Initiation	4	10.8×	0.013	BDP1, POLR1C, POLR1D, POLR2F
RNA Polymerase III Transcription	4	10.5×	0.014	BDP1, POLR1C, POLR1D, POLR2F
Transcriptional and post-translational regulation of MITF-M expression and activity	5	7.2×	0.016	CREBBP, EDNRB, KARS1, MITF, PAX3
Regulation of MITF-M dependent genes involved in invasion	2	46.0×	0.017	DIAPH1, MITF
RNA Polymerase III Chain Elongation	3	15.3×	0.020	POLR1C, POLR1D, POLR2F
Cytosolic sensors of pathogen-associated DNA	4	9.2×	0.020	POLR1C, POLR1D, CREBBP, POLR2F
RNA Polymerase III Abortive And Retractive Initiation	4	9.0×	0.021	BDP1, POLR1C, POLR1D, POLR2F
MECP2 regulates transcription factors	2	36.8×	0.024	RBFOX1, MECP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 164 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	61	37.5×	1e-79	GJB2, KCNQ4, SIX1, TMPRSS3, USH1C, USH2A, CLRN1, TSPEAR (+53 more)
sensory perception of light stimulus	9	102.8×	4e-16	USH1C, USH2A, CLRN1, CDH23, PCDH15, USH1G, WHRN, ADGRV1 (+1 more)
inner ear morphogenesis	15	27.5×	2e-15	FOXI1, KCNQ4, SIX1, USH1C, USH1G, CHD7, COL11A1, COL2A1 (+7 more)
auditory receptor cell stereocilium organization	11	56.5×	3e-15	CLRN1, CDH23, STRC, WHRN, TRIOBP, LHFPL5, PDZD7, TPRN (+3 more)
detection of mechanical stimulus involved in sensory perception of sound	10	57.1×	6e-14	STRC, WHRN, TMC1, ADGRV1, LHFPL5, COL11A1, PDZD7, PJVK (+2 more)
equilibrioception	6	88.1×	1e-09	USH1C, CLRN1, CDH23, PCDH15, USH1G, MYO7A
inner ear receptor cell differentiation	5	102.8×	2e-08	USH2A, DIAPH3, WHRN, ADGRV1, PDZD7
visual perception	16	7.8×	4e-08	TYR, USH2A, CLRN1, WFS1, CLIC5, CDH23, CABP2, ADGRV1 (+8 more)
photoreceptor cell maintenance	9	19.7×	9e-08	USH1C, USH2A, CLRN1, CDH23, PCDH15, USH1G, ADGRV1, CIB2 (+1 more)
inner ear development	8	18.3×	1e-06	BMP2, SIX1, PCDH15, ADGRV1, ESRRB, EYA4, GJB6, KCNQ1
inner ear receptor cell stereocilium organization	6	30.8×	3e-06	USH1C, USH1G, WHRN, ADGRV1, OTOGL, GRXCR1
cochlea development	7	20.0×	5e-06	CDH23, SLITRK6, GRXCR1, GATA3, KCNQ1, MYO7A, SLC26A5
inner ear auditory receptor cell differentiation	5	36.7×	2e-05	USH1C, USH2A, GSDME, MYO6, POU4F3
olfactory behavior	4	45.7×	1e-04	WFS1, SHANK1, CHD7, ATP6V1B1
electron transport coupled proton transport	3	77.1×	3e-04	MT-CYB, MT-ND4, MT-ND5
collagen fibril organization	7	9.6×	7e-04	COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6
otic vesicle development	3	51.4×	0.001	SIX1, COL2A1, GATA3
establishment of protein localization	5	13.2×	0.003	USH2A, WHRN, ADGRV1, PDZD7, FLNA
actin filament-based movement	4	19.6×	0.003	MYH14, MYH9, MYO6, MYO7A
pharyngeal system development	4	19.6×	0.003	SIX1, EYA1, GATA3, HOXA2
proteoglycan metabolic process	3	34.2×	0.004	BMP2, COL11A1, COL2A1
auditory receptor cell development	3	34.2×	0.004	TMC1, PDZD7, KCNQ1
L-arabinose metabolic process	2	102.8×	0.005	OTOGL, OTOG
positive regulation of T-helper 2 cell cytokine production	3	28.0×	0.008	NLRP3, GATA3, IL6
cochlea morphogenesis	4	14.2×	0.009	SIX1, EYA1, MYO3A, POU3F4
regulation of pH	3	25.7×	0.009	EDNRB, ATP6V1B1, SLC26A4
establishment of endothelial intestinal barrier	3	25.7×	0.009	TJP2, FASN, PTPRS
collagen-activated tyrosine kinase receptor signaling pathway	3	23.7×	0.012	COL4A3, COL4A5, COL4A6
olfactory nerve development	2	68.5×	0.012	SALL1, CHD7
vestibulocochlear nerve development	2	68.5×	0.012	SLITRK6, POU4F3

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Brimapitide, C-Terminal Acid	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcysteine, Dexamethasone, Dextrose, Ebselen, Hydroxychloroquine, Mannitol, Prednisone, Zonisamide.

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 8 · Phased (≥1): 11 · Undrugged: 64

Druggability breadth: 68 of 180 evidence-associated genes (38%) 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
GJB2	KANAMYCIN
KCNQ4	EZOGABINE
SIK3	MOMELOTINIB
TYR	ASCORBIC ACID
CACNA1D	BEPRIDIL
ABHD12	ORLISTAT
NLRP3	CLOMIPHENE
KCNT1	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1D	48	4
SIK3	25	4
NLRP3	11	4
TYR	10	4
KCNQ4	2	4
ABHD12	2	4
KCNT1	2	4
GJB2	1	4
TCOF1	1	2
POLR1C	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2
EZOGABINE	4	KCNQ4
MOMELOTINIB	4	SIK3
FEDRATINIB	4	SIK3
RUXOLITINIB	4	SIK3
DABRAFENIB	4	SIK3
VANDETANIB	4	SIK3
BOSUTINIB	4	SIK3
DASATINIB	4	CACNA1D, SIK3
MIDOSTAURIN	4	SIK3
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
BEPRIDIL	4	CACNA1D, KCNT1
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D, KCNT1
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
NLRP3	534	Binding:527, Functional:6, ADMET:1
CACNA1D	233	Binding:145, Functional:81, Toxicity:5, ADMET:2
TYR	211	Binding:209, ADMET:2
SIK3	173	Binding:173
KCNQ4	48	Binding:42, Functional:3, ADMET:2, Toxicity:1
CDK20	40	Binding:40
ABHD12	35	Binding:31, Toxicity:3, ADMET:1
IKZF2	26	Binding:26
KCNT1	24	Binding:24
BMP2	22	Binding:18, Functional:4
SIX1	12	Binding:12
ALPK3	10	Binding:10
PCDH15	9	Binding:9
TCOF1	8	Binding:8
THBS1	8	Binding:8
POLR1C	7	Binding:7
GJB2	5	Binding:5
OXR1	2	Binding:2
POLD3	1	Binding:1
VAV1	1	Binding:1
WFS1	1	Binding:1
B3GNT4	1	Binding:1
PNPLA6	1	Binding:1
DHX30	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNPT1	2.7.7.8	polyribonucleotide nucleotidyltransferase
TYR	1.14.18.1	tyrosinase
NSDHL	1.1.1.170	3beta-hydroxysteroid-4alpha-carboxylate 3-dehydrogenase (decarboxylating)
CHSY1	2.4.1.175, 2.4.1.226	glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase, N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SIK3	173
TYR	211
CACNA1D	233
NLRP3	534

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
KANAMYCIN	4	GJB2
EZOGABINE	4	KCNQ4
MOMELOTINIB	4	SIK3
FEDRATINIB	4	SIK3
RUXOLITINIB	4	SIK3
DABRAFENIB	4	SIK3
VANDETANIB	4	SIK3
BOSUTINIB	4	SIK3
DASATINIB	4	CACNA1D, SIK3
MIDOSTAURIN	4	SIK3
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
BEPRIDIL	4	CACNA1D, KCNT1
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D, KCNT1
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	GJB2, KCNQ4, SIK3, TYR, CACNA1D, ABHD12, NLRP3, KCNT1
B	Phased (≥1) drug, not yet approved	3	TCOF1, POLR1C, CDK20
C	Druggable family + PDB, no drug	1	NSDHL
D	Druggable family + AlphaFold only, no drug	7	SEMA3F, TMPRSS3, USH2A, CHSY1, ADGRV1, ALPK3, CATSPER2
E	Difficult family or no structure, no drug	56	FOXI1, SPATC1L, IKZF2, THOC1, POLD3, PNPT1, FMN1, GAS2, SALL1, BMP2 (+46 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXI1	0	GJB2
WFS1	1	GJB2
CABP2	0	CACNA1D
DMBX1	0	SIK3
SPATC1L	0	—
IKZF2	26	—
THOC1	0	—
POLD3	1	—
PNPT1	0	—
FMN1	0	—
GAS2	0	—
SALL1	0	—
BMP2	22	—
SEMA3F	0	—
SIX1	12	—
BRCA2	0	—
SMPX	0	—
THBS1	8	—
TJP2	0	—
TMPRSS3	0	—
TSC1	0	—
USH1C	0	—
USH2A	0	—
CLRN1	0	—
VAV1	1	—
TSPEAR	0	—
NSDHL	0	—
CLIC5	0	—
BDP1	0	—
CDH23	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 602.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	559
PHASE2	12
PHASE1	9
PHASE4	5
PHASE1/PHASE2	5
PHASE2/PHASE3	4
PHASE3	4
EARLY_PHASE1	4

Top trials by phase / activity

NCT	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
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
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
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
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
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
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
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
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
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
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)
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
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
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
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GINKGO	4	2
DEXTROSE	4	1
FIBRINOGEN I 125	4	1
HYALURONIC ACID	4	1
SODIUM THIOSULFATE	4	1
BRIMAPITIDE, C-TERMINAL ACID	3	2
EBSELEN	3	2
ANCROD	3	1
AUTOLOGOUS CORD BLOOD	3	1
DISUFENTON SODIUM	3	1
CHOLESTEROL	2	1
CHEMBL5435500	0	1
CHEMBL1867358	0	1
CHEMBL3184306	0	1
CHEMBL5268979	0	1