Sensorineural hearing loss disorder

Summary

Sensorineural hearing loss disorder (MONDO:0020678) is a disease caused by variants in OXR1 and PKHD1L1, with 75 cohort genes (30 GWAS associations across 4 studies) and 89 clinical trials. The dominant Reactome pathway is Sensory processing of sound by outer hair cells of the cochlea (7 cohort genes). Top therapeutic interventions include valganciclovir, anakinra, and deferiprone.

At a glance

• Causal genes: OXR1 (GenCC Strong), PKHD1L1 (GenCC Strong)
• Cohort genes: 75
• GWAS associations: 30
• ClinVar variants: 92
• Clinical trials: 89

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sensorineural hearing loss disorder
Mondo ID	MONDO:0020678
EFO	EFO:1001176
DOID	DOID:10003
NCIT	C26739
SNOMED CT	60700002
UMLS	C0018784
MedGen	9164
Is cancer (heuristic)	no

Also known as: sensorineural deafness · sensorineural hearing loss · sensorineural hearing loss disorder · SNHL

Data availability: 92 ClinVar variants · 1 ClinGen variant curation · 30 GWAS associations (4 studies) · 6 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (10): Johanson-Blizzard syndrome, noise induced hearing loss, nonsyndromic genetic hearing loss, sudden 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 (3): sudden sensorineural hearing loss, presbycusis, platinum-induced ototoxicity

Genetics & variants

GWAS landscape

30 GWAS associations across 4 studies. Top hits map to 22 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs6803403	1e-32	CFAP20DC-DT, FHIT	?	0.11
rs72759216	3e-25	LHX2 - NEK6	?	3.52
rs6684586	2e-20	TRMT1L	?	0.2
rs246887	2e-19	MEGF10	?	0.12
rs184005082	3e-10	AARS2 - SPATS1	?	17.31
rs79150545	8e-09	SAMD5	?	5.91
rs537646588	9e-09	MYT1L - LINC01250	?	91.45
rs80344881	2e-08	ID4 - RPL29P17	?	7.46
rs10284225	7e-08	DMD	?
rs574517306	9e-08	IPCEF1 - CNKSR3	?	12.47
rs78719745	9e-08	RNU6-573P - ARAP2	?	10.17
rs190546757	1e-07	KCNQ3	?	26.17
rs191797614	1e-07	LINC02391	?	10.27
rs139768353	1e-07	EXOC2 - LINC01622	?	36.64
rs78023951	1e-07	ANKRD26P2 - STOML3	?	35.59
rs374180147	2e-07	ME2P1 - LINC01242	?	76.86
rs570999833	2e-07	CNTN5	?	26.46
rs181558197	2e-07	BMS1	?	27.43
rs141094288	2e-07	SGPL1, LINC02622	?	13.28
rs532757028	3e-07	CCM2	?	22.27
rs553208041	3e-07	KSR2	?	23.9
rs186662456	4e-07	LHFPL6	?	21.18
rs147716413	5e-07	NPHP3, NPHP3-ACAD11	?	16.98
rs146954815	6e-07	DHRS9 - UBE2V1P6	?	16.77
rs140008019	7e-07	IFNG-AS1	?	5.77
rs200995605	7e-07	SLC10A2 - LINC01309	?	14.01
rs139237147	7e-07	ALG9	?	9.95
rs142776659	7e-07	ITPR2	?	10.49
rs75786794	9e-07	PRKAG2	?	18.69
rs190158134	9e-07	ATXN7L1	?	10.62

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90043836	Jiang L	2021	585	455,763	A generalized linear mixed model association tool for biobank-scale data.
GCST90651789	Liu TY	2025	351	224,789	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90837325	Kitoh R	2026	192	15,302	Inflammation and Oxidative-Stress Pathways Are Associated with Idiopathic Sudden Hearing Loss: A Genome-Wide Association Study in 15,494 Japanese Individuals.
GCST90043834	Jiang L	2021	129	456,219	A generalized linear mixed model association tool for biobank-scale data.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	28

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	24

Functional consequences

Consequence	Count
intron_variant	20
intergenic_variant	7
3_prime_UTR_variant	1
missense_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs6803403	3	59754193	G>A	0.05	intron_variant	CFAP20DC-DT, FHIT	1e-32	Tier 4: intronic/intergenic
rs72759216	9	124092243	C>T	0.05	intergenic_variant	LHX2 - NEK6	3e-25	Tier 4: intronic/intergenic
rs6684586	1	185145705	G>A	0.05	intron_variant	TRMT1L	2e-20	Tier 4: intronic/intergenic
rs246887	5	127320057	C>G,T	0.05	intron_variant	MEGF10	2e-19	Tier 4: intronic/intergenic
rs184005082	6	44337925	G>T		intron_variant	AARS2 - SPATS1	3e-10	Tier 4: intronic/intergenic
rs79150545	6	147569889	A>G,T	0.05	3_prime_UTR_variant	SAMD5	8e-09	Tier 2: splice/UTR
rs537646588	2	2732811	A>T		intron_variant	MYT1L - LINC01250	9e-09	Tier 4: intronic/intergenic
rs80344881	6	19931050	T>C,G		intergenic_variant	ID4 - RPL29P17	2e-08	Tier 4: intronic/intergenic
rs10284225	X	33236821	T>C	0.05	intron_variant	DMD	7e-08	Tier 4: intronic/intergenic
rs574517306	6	154371377	AT>A		intron_variant	IPCEF1 - CNKSR3	9e-08	Tier 4: intronic/intergenic
rs78719745	4	35868084	A>C		intergenic_variant	RNU6-573P - ARAP2	9e-08	Tier 4: intronic/intergenic
rs190546757	8	132252184	G>A		intron_variant	KCNQ3	1e-07	Tier 4: intronic/intergenic
rs191797614	12	92308099	G>A,C,T		intron_variant	LINC02391	1e-07	Tier 4: intronic/intergenic
rs139768353	6	915373	T>C		intergenic_variant	EXOC2 - LINC01622	1e-07	Tier 4: intronic/intergenic
rs78023951	13	38938554	A>G		intergenic_variant	ANKRD26P2 - STOML3	1e-07	Tier 4: intronic/intergenic
rs374180147	9	29879338	C>T		intron_variant	ME2P1 - LINC01242	2e-07	Tier 4: intronic/intergenic
rs570999833	11	100133248	C>T		intron_variant	CNTN5	2e-07	Tier 4: intronic/intergenic
rs181558197	10	42823717	G>A		missense_variant	BMS1	2e-07	Tier 1: coding
rs141094288	10	70930752	A>T		non_coding_transcript_exon_variant	SGPL1, LINC02622	2e-07	Tier 4: intronic/intergenic
rs532757028	7	45025554	A>G,T		intron_variant	CCM2	3e-07	Tier 4: intronic/intergenic
rs553208041	12	117821043	A>G		intron_variant	KSR2	3e-07	Tier 4: intronic/intergenic
rs186662456	13	39231957	G>A,C		intergenic_variant	LHFPL6	4e-07	Tier 4: intronic/intergenic
rs147716413	3	132685152	T>C		intron_variant	NPHP3, NPHP3-ACAD11	5e-07	Tier 4: intronic/intergenic
rs146954815	2	169097042	C>T		intron_variant	DHRS9 - UBE2V1P6	6e-07	Tier 4: intronic/intergenic
rs140008019	12	68192806	A>G		intergenic_variant	IFNG-AS1	7e-07	Tier 4: intronic/intergenic
rs200995605	13	103178991	G>A		intron_variant	SLC10A2 - LINC01309	7e-07	Tier 4: intronic/intergenic
rs139237147	11	111870909	T>C		intron_variant	ALG9	7e-07	Tier 4: intronic/intergenic
rs142776659	12	26712590	G>A,C		intron_variant	ITPR2	7e-07	Tier 4: intronic/intergenic
rs75786794	7	151606889	A>G		intron_variant	PRKAG2	9e-07	Tier 4: intronic/intergenic
rs190158134	7	105622451	G>A,T		intron_variant	ATXN7L1	9e-07	Tier 4: intronic/intergenic

ClinVar germline variants

92 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 25 pathogenic, 16 conflicting classifications of pathogenicity, 14 likely pathogenic, 6 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267809	46;XY;t(8;9)(q13;p22)dn		Pathogenic	criteria provided, single submitter
268006	46;XY;t(6;11)(p12.3;p14.2)dn		Pathogenic	criteria provided, single submitter
374094	NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr)	AIFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984398	NM_020632.3(ATP6V0A4):c.707AGA[1] (p.Lys237del)	ATP6V0A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
691620	NM_003672.4(CDC14A):c.1351_1352del (p.Ala451fs)	CDC14A	Pathogenic	criteria provided, single submitter
1810397	NM_022124.6(CDH23):c.6571_6593del (p.Thr2191fs)	CDH23	Pathogenic	criteria provided, single submitter
444219	NM_022124.6(CDH23):c.2866G>A (p.Glu956Lys)	CDH23	Pathogenic	reviewed by expert panel
372269	NM_001330691.3(CEP78):c.893-1G>A	CEP78	Pathogenic	no assertion criteria provided
372270	NM_001330691.3(CEP78):c.534del (p.Lys179fs)	CEP78	Pathogenic	criteria provided, single submitter
984395	NM_001146079.2(CLDN14):c.40_41insTGGTGCACGGCCGTGCA (p.Ser14fs)	CLDN14	Pathogenic	criteria provided, single submitter
984393	NM_001851.6(COL9A1):c.2644del (p.Val882fs)	COL9A1	Pathogenic	criteria provided, single submitter
1472670	NM_001012426.2(FOXP4):c.1540G>A (p.Ala514Thr)	FOXP4	Pathogenic	criteria provided, multiple submitters, no conflicts
17001	NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17002	NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)	GJB2	Pathogenic	reviewed by expert panel
17020	NM_004004.6(GJB2):c.148G>A (p.Asp50Asn)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
14950	NM_000601.6(HGF):c.482+1986_482+1988del	HGF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560389	NM_005548.3(KARS1):c.1354del (p.Leu452fs)	KARS1	Pathogenic	criteria provided, single submitter
547164	NM_000219.6(KCNE1):c.51G>A (p.Trp17Ter)	KCNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
9589	NC_012920.1(MT-TL1):m.3243A>G	MT-TL1	Pathogenic	reviewed by expert panel
655296	NM_017433.5(MYO3A):c.1370_1371del (p.Arg457fs)	MYO3A	Pathogenic	criteria provided, multiple submitters, no conflicts
984399	NM_000260.4(MYO7A):c.5442T>G (p.Tyr1814Ter)	MYO7A	Pathogenic	criteria provided, single submitter
41236	NM_006158.5(NEFL):c.293A>G (p.Asn98Ser)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523510	NM_015100.4(POGZ):c.2771del (p.Pro924fs)	POGZ	Pathogenic	criteria provided, single submitter
590798	NM_020975.6(RET):c.1280_1281del (p.Val427fs)	RET	Pathogenic	criteria provided, single submitter
972899	NM_001046.3(SLC12A2):c.2962C>T (p.Pro988Ser)	SLC12A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2202880	NM_006996.3(SLC19A2):c.196G>T (p.Glu66Ter)	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
43566	NM_000441.2(SLC26A4):c.716T>A (p.Val239Asp)	SLC26A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1676769	NM_004604.5(STX4):c.232+6T>C	STX4	Pathogenic/Likely pathogenic	no assertion criteria provided
984396	NM_147196.3(TMIE):c.122_125dup (p.Pro43fs)	TMIE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1677001	NM_032805.3(ZSCAN10):c.2050del (p.His684fs)	ZSCAN10	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 132 · 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
HCRTR1	Strong	Autosomal recessive	sensorineural hearing loss disorder	4
OXR1	Strong	Autosomal recessive	sensorineural hearing loss disorder	4
PKHD1L1	Strong	Autosomal recessive	sensorineural hearing loss disorder	2
FOXF2	Moderate	Autosomal recessive	sensorineural hearing loss disorder
THOC1	Moderate	Autosomal dominant	hearing loss disorder	2
ANKRD24	Limited	Autosomal recessive	sensorineural hearing loss disorder	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCP2	Orphanet:163684	Leukoencephalopathy-dystonia-motor neuropathy syndrome
SLC12A2	Orphanet:633021	SLC12A2-related autosomal recessive neonatal-developmental delay-intellectual disability-feeding difficulty-sensorineural deafness syndrome
SLC12A2	Orphanet:633024	SLC12A2-related autosomal dominant infantile-developmental delay-intellectual disability-sensorineural deafness syndrome
SLC19A2	Orphanet:49827	Thiamine-responsive megaloblastic anemia syndrome
BRF1	Orphanet:444072	Cerebellar-facial-dental syndrome
TOP3A	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
TOP3A	Orphanet:508512	Intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
ESPN	Orphanet:231169	Usher syndrome type 1
ESPN	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
MRPS7	Orphanet:457223	Syndromic sensorineural deafness due to combined oxidative phosphorylation defect
TMC1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TMC1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CDC14A	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
RRM2B	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
RRM2B	Orphanet:255235	Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy
RRM2B	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
RRM2B	Orphanet:329336	Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
RRM2B	Orphanet:480	Kearns-Sayre syndrome
GIPC3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
USP48	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
USP48	Orphanet:96253	Cushing disease
POGZ	Orphanet:468678	White-Sutton syndrome
CLCNKA	Orphanet:89938	Bartter syndrome type 4
CLDN14	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
COL9A1	Orphanet:166002	Multiple epiphyseal dysplasia due to collagen 9 anomaly
COL9A1	Orphanet:250984	Autosomal recessive Stickler syndrome
MYH14	Orphanet:397744	MYH14-related peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome
MYH14	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CEP78	Orphanet:231183	Usher syndrome type 3
NARS2	Orphanet:444458	Combined oxidative phosphorylation defect type 24

Cohort genes → proteins

75 cohort genes, 72 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OXR1	HGNC:15822	ENSG00000164830	Q8N573	Oxidation resistance protein 1	gencc
THOC1	HGNC:19070	ENSG00000079134	Q96FV9	THO complex subunit 1	gencc
PKHD1L1	HGNC:20313	ENSG00000205038	Q86WI1	Fibrocystin-L	gencc
ANKRD24	HGNC:29424	ENSG00000089847	Q8TF21	Ankyrin repeat domain-containing protein 24	gencc
FOXF2	HGNC:3810	ENSG00000137273	Q12947	Forkhead box protein F2	gencc
HCRTR1	HGNC:4848	ENSG00000121764	O43613	Orexin/Hypocretin receptor type 1	gencc
SCP2	HGNC:10606	ENSG00000116171	P22307	Sterol carrier protein 2	clinvar
SLC12A2	HGNC:10911	ENSG00000064651	P55011	Solute carrier family 12 member 2	clinvar
SLC19A2	HGNC:10938	ENSG00000117479	O60779	Thiamine transporter 1	clinvar
STX4	HGNC:11439	ENSG00000103496	Q12846	Syntaxin-4	clinvar
BRF1	HGNC:11551	ENSG00000185024	Q92994	Transcription factor IIIB 90 kDa subunit	clinvar
TCF19	HGNC:11629	ENSG00000137310	Q9Y242	Transcription factor 19	clinvar
TFAM	HGNC:11741	ENSG00000108064	Q00059	Transcription factor A, mitochondrial	clinvar
TOP3A	HGNC:11992	ENSG00000177302	Q13472	DNA topoisomerase 3-alpha	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
ZSCAN10	HGNC:12997	ENSG00000130182	Q96SZ4	Zinc finger and SCAN domain-containing protein 10	clinvar
ESPN	HGNC:13281	ENSG00000187017	B1AK53	Espin	clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	clinvar
MRPS7	HGNC:14499	ENSG00000125445	Q9Y2R9	Small ribosomal subunit protein uS7m	clinvar
PLSCR4	HGNC:16497	ENSG00000114698	Q9NRQ2	Phospholipid scramblase 4	clinvar
TMC1	HGNC:16513	ENSG00000165091	Q8TDI8	Transmembrane channel-like protein 1	clinvar
CTDSP2	HGNC:17077	ENSG00000175215	O14595	Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2	clinvar
CDC14A	HGNC:1718	ENSG00000079335	Q9UNH5	Dual specificity protein phosphatase CDC14A	clinvar
RRM2B	HGNC:17296	ENSG00000048392	Q7LG56	Ribonucleoside-diphosphate reductase subunit M2 B	clinvar
GIPC3	HGNC:18183	ENSG00000179855	Q8TF64	PDZ domain-containing protein GIPC3	clinvar
USP48	HGNC:18533	ENSG00000090686	Q86UV5	Ubiquitin carboxyl-terminal hydrolase 48	clinvar
POGZ	HGNC:18801	ENSG00000143442	Q7Z3K3	Pogo transposable element with ZNF domain	clinvar
USP31	HGNC:20060	ENSG00000103404	Q70CQ4	Ubiquitin carboxyl-terminal hydrolase 31	clinvar
CLCNKA	HGNC:2026	ENSG00000186510	P51800	Chloride channel protein ClC-Ka	clinvar
CLDN14	HGNC:2035	ENSG00000159261	O95500	Claudin-14	clinvar
FOXP4	HGNC:20842	ENSG00000137166	Q8IVH2	Forkhead box protein P4	clinvar
CARMIL1	HGNC:21581	ENSG00000079691	Q5VZK9	F-actin-uncapping protein LRRC16A	clinvar
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	clinvar
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	clinvar
COL9A1	HGNC:2217	ENSG00000112280	P20849	Collagen alpha-1(IX) chain	clinvar
MYH14	HGNC:23212	ENSG00000105357	Q7Z406	Myosin-14	clinvar
CEP78	HGNC:25740	ENSG00000148019	Q5JTW2	Centrosomal protein of 78 kDa	clinvar
NARS2	HGNC:26274	ENSG00000137513	Q96I59	Asparaginyl-tRNA synthetase	clinvar
COX18	HGNC:26801	ENSG00000163626	Q8N8Q8	Cytochrome c oxidase assembly protein COX18, mitochondrial	clinvar
DBH	HGNC:2689	ENSG00000123454	P09172	Dopamine beta-hydroxylase	clinvar
SPNS2	HGNC:26992	ENSG00000183018	Q8IVW8	Sphingosine-1-phosphate transporter SPNS2	clinvar
GSDME	HGNC:2810	ENSG00000105928	O60443	Gasdermin-E	clinvar
TOP1MT	HGNC:29787	ENSG00000184428	Q969P6	DNA topoisomerase I, mitochondrial	clinvar
SLC52A2	HGNC:30224	ENSG00000185803	Q9HAB3	Solute carrier family 52, riboflavin transporter, member 2	clinvar
TMIE	HGNC:30800	ENSG00000181585	Q8NEW7	Transmembrane inner ear expressed protein	clinvar
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	clinvar
EDN3	HGNC:3178	ENSG00000124205	P14138	Endothelin-3	clinvar
CBY3	HGNC:33278	ENSG00000204659	A6NI87	Sperm annulus positioning complex subunit Chibby3	clinvar
FOXI1	HGNC:3815	ENSG00000168269	Q12951	Forkhead box protein I1	clinvar
USH2A-AS2	HGNC:40605	ENSG00000233620		USH2A antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OXR1	Oxidation resistance protein 1	May be involved in protection from oxidative damage.
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.
PKHD1L1	Fibrocystin-L	Component of hair-cell stereocilia coat.
ANKRD24	Ankyrin repeat domain-containing protein 24	Component of the stereocilia rootlet in hair cells of inner ear.
FOXF2	Forkhead box protein F2	Probable transcription activator for a number of lung-specific genes.
HCRTR1	Orexin/Hypocretin receptor type 1	G-protein coupled receptor that binds the neuropeptide orexin-A with high affinity, and orexin-B with lower affinity, two peptides derived from a common precursor, prepro-orexin.
SCP2	Sterol carrier protein 2	Plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids.
SLC12A2	Solute carrier family 12 member 2	Cation-chloride cotransporter which mediates the electroneutral transport of chloride, potassium and/or sodium ions across the membrane.
SLC19A2	Thiamine transporter 1	High-affinity transporter for the intake of thiamine.
STX4	Syntaxin-4	Plasma membrane t-SNARE that mediates docking of transport vesicles.
BRF1	Transcription factor IIIB 90 kDa subunit	General activator of RNA polymerase which utilizes different TFIIIB complexes at structurally distinct promoters.
TCF19	Transcription factor 19	Potential transcription factor that may play a role in the regulation of genes involved in cell cycle G1/S transition.
TFAM	Transcription factor A, mitochondrial	Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation.
TOP3A	DNA topoisomerase 3-alpha	Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex.
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.
ZSCAN10	Zinc finger and SCAN domain-containing protein 10	Embryonic stem (ES) cell-specific transcription factor required to maintain ES cell pluripotency.
ESPN	Espin	Multifunctional actin-bundling protein.
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
PLSCR4	Phospholipid scramblase 4	Catalyzes metal ion-induced ATP-independent rapid bidirectional and non-specific movement of phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer leaflet of the plasma membrane and participates in the redistribut…
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.
CTDSP2	Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2	Preferentially catalyzes the dephosphorylation of ‘Ser-5’ within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A.
CDC14A	Dual specificity protein phosphatase CDC14A	Dual-specificity phosphatase.
RRM2B	Ribonucleoside-diphosphate reductase subunit M2 B	Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner.
GIPC3	PDZ domain-containing protein GIPC3	Required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion.
USP48	Ubiquitin carboxyl-terminal hydrolase 48	Deubiquitinase that recognizes and hydrolyzes the peptide bond at the C-terminal Gly of ubiquitin.
POGZ	Pogo transposable element with ZNF domain	Plays a role in mitotic cell cycle progression and is involved in kinetochore assembly and mitotic sister chromatid cohesion.
USP31	Ubiquitin carboxyl-terminal hydrolase 31	Deubiquitinase that recognizes and hydrolyzes the peptide bond at the C-terminal Gly of ubiquitin.
CLCNKA	Chloride channel protein ClC-Ka	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
CLDN14	Claudin-14	Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
FOXP4	Forkhead box protein P4	Transcriptional repressor that represses lung-specific expression.
CARMIL1	F-actin-uncapping protein LRRC16A	Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments.
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL9A1	Collagen alpha-1(IX) chain	Structural component of hyaline cartilage and vitreous of the eye.
MYH14	Myosin-14	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
CEP78	Centrosomal protein of 78 kDa	Centriole wall protein that localizes to mature centrioles and regulates centriole and cilia biogenesis.
NARS2	Asparaginyl-tRNA synthetase	Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the asparagine amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis.
COX18	Cytochrome c oxidase assembly protein COX18, mitochondrial	Mitochondrial membrane insertase required for the translocation of the C-terminus of cytochrome c oxidase subunit II (MT-CO2/COX2) across the mitochondrial inner membrane.
DBH	Dopamine beta-hydroxylase	Catalyzes the hydroxylation of dopamine to noradrenaline (also known as norepinephrine), and is thus vital for regulation of these neurotransmitters.
SPNS2	Sphingosine-1-phosphate transporter SPNS2	Lipid transporter that specifically mediates export of sphingosine-1-phosphate (sphing-4-enine 1-phosphate, S1P) and sphinganine-1-phosphate in the lymph, thereby playing a role in lymphocyte trafficking.
GSDME	Gasdermin-E	Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis.
TOP1MT	DNA topoisomerase I, mitochondrial	Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA by transiently cleaving and rejoining one strand of the DNA duplex.
SLC52A2	Solute carrier family 52, riboflavin transporter, member 2	Plasma membrane transporter mediating the uptake by cells of the water soluble vitamin B2/riboflavin that plays a key role in biochemical oxidation-reduction reactions of the carbohydrate, lipid, and amino acid metabolism.
TMIE	Transmembrane inner ear expressed protein	Auxiliary subunit of the mechanotransducer (MET) non-specific cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.
AFG3L2	Mitochondrial inner membrane m-AAA protease component AFG3L2	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
EDN3	Endothelin-3	Endothelins are endothelium-derived vasoconstrictor peptides.
CBY3	Sperm annulus positioning complex subunit Chibby3	Plays a key role in the correct positioning of the annulus, a septin-based ring structure in the sperm flagellum, serving both as a physical barrier and a membrane diffusion barrier that separates the midpiece (MP) from the principal piece…
FOXI1	Forkhead box protein I1	Transcriptional activator required for the development of normal hearing, sense of balance and kidney function.
GABRA1	Gamma-aminobutyric acid receptor subunit alpha-1	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GGPS1	Geranylgeranyl pyrophosphate synthase	Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.

Protein-family classification

Druggable: 28 · Difficult: 15 · Unknown: 32 · Druggable fraction: 0.37

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
Phosphatase	4	4.5×	0.114
Enzyme (other)	12	1.9×	0.114
Transporter	3	3.1×	0.265
Protease	4	1.9×	0.409
Scaffold/PPI	6	1.4×	0.585
Ion channel	1	1.5×	0.888
Transcription factor	9	1.0×	0.888
Other/Unknown	32	0.8×	0.992
Kinase	2	0.7×	0.992
Antibody/Immunoglobulin	1	0.4×	0.992
GPCR	1	0.3×	0.992

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OXR1	Other/Unknown	no		TLDc_dom, LysM, LysM_dom_sf
THOC1	Other/Unknown	no		Death_dom, DEATH-like_dom_sf, THO_THOC1
PKHD1L1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Cupredoxin
ANKRD24	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, RAI14/UACA
FOXF2	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
HCRTR1	GPCR	yes		Orexin_rcpt, GPCR_Rhodpsn, OX1R
SCP2	Enzyme (other)	yes	2.3.1.176	SCP2_sterol-bd_dom, Thiolase-like, Thiolase_CS
SLC12A2	Other/Unknown	no		SLC12A1/SLC12A2, NKCC1, AA-permease/SLC12A_dom
SLC19A2	Transporter	yes		Folate_carrier, ThTr-1, MFS_trans_sf
STX4	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
BRF1	Transcription factor	no		TFIIB, BRF1_TBP-bd_dom, Znf_TFIIB
TCF19	Transcription factor	no		FHA_dom, Znf_PHD, SMAD_FHA_dom_sf
TFAM	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, HMGB
TOP3A	Transcription factor	no		Topo_IA, Topo_IA_2, Topo_IA_DNA-bd_dom
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
ZSCAN10	Transcription factor	no		SCAN_dom, Znf_C2H2_type, Znf_C2H2_sf
ESPN	Scaffold/PPI	no		Ankyrin_rpt, WH2_dom, Ankyrin_rpt-contain_sf
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
MRPS7	Other/Unknown	no		Ribosomal_uS7, Ribosomal_uS7_dom, Ribosomal_uS7_dom_sf
PLSCR4	Enzyme (other)	yes	7.6.2.1	Scramblase
TMC1	Other/Unknown	no		TMC_dom, TMC
CTDSP2	Phosphatase	yes		FCP1_dom, Dullard_phosphatase, HAD_sf
CDC14A	Phosphatase	yes		Tyr_Pase_dom, Tyr_Pase_cat, Tyr_Pase_AS
RRM2B	Enzyme (other)	yes	1.17.4.1	RNR_small_fam, Ferritin-like_SF, RNR-like
GIPC3	Scaffold/PPI	no		PDZ, GIPC1/2/3, PDZ_sf
USP48	Protease	yes		Ubiquitin-like_dom, Peptidase_C19_UCH, Pept_C19_DUSP
POGZ	Transcription factor	no		DDE_SF_endonuclease_dom, HTH_CenpB_DNA-bd_dom, Homeodomain-like_sf
USP31	Protease	yes		Peptidase_C19_UCH, USP_CS, USP
CLCNKA	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
CLDN14	Other/Unknown	no		PMP22/EMP/MP20/Claudin, Claudin, Claudin_CS
FOXP4	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC
CARMIL1	Other/Unknown	no		Leu-rich_rpt, PH-like_dom_sf, CARMIL_C
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL9A1	Other/Unknown	no		Collagen, ConA-like_dom_sf, TSPN-like_N
MYH14	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
CEP78	Other/Unknown	no		Leu-rich_rpt, Cep78, LRR_dom_sf
NARS2	Enzyme (other)	yes	6.1.1.22	Asp/Asn-tRNA-synth_IIb, Aa-tRNA-synt_II, NA-bd_OB_tRNA
COX18	Other/Unknown	no		YidC/ALB3/OXA1/COX18, YidC/Oxa/ALB_C
DBH	Enzyme (other)	yes	1.14.17.1	Cu2_ascorb_mOase_N, DBH-like, DOMON_domain
SPNS2	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
GSDME	Other/Unknown	no		Gasdermin_pore, Gasdermin_PUB, GSDME
TOP1MT	Enzyme (other)	yes	5.6.2.1	TopoI, TopoI_DNA-bd_euk, DNA_brk_join_enz
SLC52A2	Other/Unknown	no		Riboflavin_transptr
TMIE	Other/Unknown	no		TMIE
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
EDN3	Other/Unknown	no		Endothln-like_toxin, Endothelin_toxin_CS, Endothelin
CBY3	Other/Unknown	no		Chibby_fam
FOXI1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
USH2A-AS2	Other/Unknown	no

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)	0
broad (>20)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	7
primordial germ cell in gonad	7
apex of heart	6
right hemisphere of cerebellum	6
ventricular zone	6
male germ line stem cell (sensu Vertebrata) in testis	6
stromal cell of endometrium	6
calcaneal tendon	5
right uterine tube	5
oocyte	5
endothelial cell	5
cerebellar hemisphere	4
jejunal mucosa	4
right lobe of liver	4
left testis	4
adult mammalian kidney	4
metanephros cortex	4
lateral nuclear group of thalamus	3
cerebellar cortex	3
left lobe of thyroid gland	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OXR1	287	ubiquitous	marker	pons, calcaneal tendon, lateral nuclear group of thalamus
THOC1	293	ubiquitous	marker	calcaneal tendon, cerebellar hemisphere, cerebellar cortex
PKHD1L1	180	broad	marker	right uterine tube, left lobe of thyroid gland, oviduct epithelium
ANKRD24	159	tissue_specific	marker	right frontal lobe, Brodmann (1909) area 9, anterior cingulate cortex
FOXF2	200	broad	yes	periodontal ligament, lower esophagus muscularis layer, lower esophagus
HCRTR1	113	tissue_specific	yes	vastus lateralis, quadriceps femoris, apex of heart
SCP2	295	ubiquitous	marker	jejunal mucosa, esophagus squamous epithelium, right lobe of liver
SLC12A2	277	ubiquitous	marker	palpebral conjunctiva, parotid gland, inferior vagus X ganglion
SLC19A2	282	ubiquitous	marker	secondary oocyte, oocyte, gastrocnemius
STX4	288	ubiquitous	marker	C1 segment of cervical spinal cord, granulocyte, skin of leg
BRF1	198	ubiquitous	marker	sural nerve, right uterine tube, right hemisphere of cerebellum
TCF19	133	ubiquitous	yes	primordial germ cell in gonad, ventricular zone, lymph node
TFAM	284	ubiquitous	marker	right testis, left testis, secondary oocyte
TOP3A	134	ubiquitous	yes	blood, ganglionic eminence, ventricular zone
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
ZSCAN10	75	tissue_specific	marker	primordial germ cell in gonad, cerebellar vermis, bone marrow cell
ESPN	184	broad	marker	right testis, left testis, right uterine tube
CDH23	161	broad	marker	ventricular zone, left ovary, right ovary
MRPS7	289	ubiquitous	marker	gastrocnemius, apex of heart, heart left ventricle
PLSCR4	281	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, calcaneal tendon
TMC1	150		marker	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, primordial germ cell in gonad
CTDSP2	295	ubiquitous	marker	mucosa of stomach, stromal cell of endometrium, descending thoracic aorta
CDC14A	222	ubiquitous	marker	sperm, male germ cell, buccal mucosa cell
RRM2B	254	ubiquitous	marker	secondary oocyte, oocyte, deltoid
GIPC3	157	tissue_specific	yes	apex of heart, stromal cell of endometrium, lower esophagus muscularis layer
USP48	292	ubiquitous	marker	calcaneal tendon, cerebellar hemisphere, right hemisphere of cerebellum
POGZ	298	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere
USP31	251	ubiquitous	marker	inferior vagus X ganglion, secondary oocyte, cauda epididymis
CLCNKA	130	tissue_specific	marker	metanephros cortex, adult mammalian kidney, left lobe of thyroid gland
CLDN14	84	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 51.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL6	9,239
MRPS7	5,544
AIFM1	4,780
TFAM	4,690
KARS1	4,681
NEFL	4,644
AFG3L2	4,260
RET	4,203
HGF	3,844
LARS1	3,514

Intra-cohort edges

A	B	Sources
AFG3L2	AIFM1	intact
ANKRD24	GIPC3	string_interaction
ATP6V0A4	FOXI1	string_interaction
CDH23	ESPN	string_interaction
CDH23	GJB2	string_interaction
CDH23	MYH14	string_interaction
CDH23	MYO15A	string_interaction
CDH23	MYO3A	string_interaction
CDH23	TMC1	string_interaction
CDH23	TMIE	string_interaction
CDH23	USP31	string_interaction
CLDN14	GJB2	string_interaction
CLDN14	SLC26A4	string_interaction
CLDN14	TMC1	string_interaction
CLDN14	TMIE	string_interaction
COL11A1	COL9A1	string_interaction
EDN3	RET	string_interaction
ESPN	GJB2	string_interaction
ESPN	MYO15A	string_interaction
ESPN	MYO3A	string_interaction
FOXI1	GJB2	string_interaction
FOXI1	SLC26A4	string_interaction
GIPC3	MYO15A	string_interaction
GIPC3	MYO3A	string_interaction
GIPC3	TMC1	string_interaction
GIPC3	TMIE	string_interaction
GJB2	MYH14	string_interaction
GJB2	MYO15A	string_interaction
GJB2	SLC26A4	string_interaction
GJB2	TMC1	string_interaction
GJB2	TMIE	string_interaction
GJB2	WFS1	string_interaction
HARS2	KARS1	string_interaction
HARS2	NARS2	string_interaction
HCRTR1	OXR1	string_interaction
KARS1	LARS1	string_interaction
KARS1	MYH14	string_interaction
MYO15A	SLC26A4	string_interaction
MYO15A	TMC1	string_interaction
MYO15A	TMIE	string_interaction
MYO3A	TMC1	string_interaction
POGZ	ZSCAN10	string_interaction
PTPRQ	TMC1	string_interaction
PTPRQ	USP31	string_interaction
PTPRR	RET	biogrid_interaction, intact
SLC19A2	WFS1	string_interaction
SLC26A4	TMC1	string_interaction
SLC26A4	TMIE	string_interaction
TMC1	TMIE	string_interaction
TMC1	WFS1	string_interaction

Structural data

PDB: 44 · AlphaFold-only: 28 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRA1	P14867	86
MRPS7	Q9Y2R9	77
HGF	P14210	36
RET	P07949	34
AIFM1	O95831	26
GJB2	P29033	24
SPNS2	Q8IVW8	18
IL6	P05231	17
TFAM	Q00059	16
HCRTR1	O43613	14
SLC12A2	P55011	14
KARS1	Q15046	14
GGPS1	O95749	9
LARS1	Q9P2J5	7
CDH23	Q9H251	6
THOC1	Q96FV9	5
COL9A1	P20849	5
KCNE1	P15382	5
MT-CYB	P00156	5
RRM2B	Q7LG56	3
POGZ	Q7Z3K3	3
CARMIL1	Q5VZK9	3
GSDME	O60443	3
LMX1A	Q8TE12	3
SCP2	P22307	2
SLC19A2	O60779	2
TOP3A	Q13472	2
MYH14	Q7Z406	2
AFG3L2	Q9Y4W6	2
ATP6V0A4	Q9HBG4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NARS2	Q96I59	91.59
TOP1MT	Q969P6	91.07
HARS2	P49590	88.44
GIPC3	Q8TF64	85.45
COX18	Q8N8Q8	83.42
SLC26A4	O43511	82.72
USP48	Q86UV5	81.44
CLDN14	O95500	80.00
STX4	Q12846	78.38
WFS1	O76024	73.85
CDC14A	Q9UNH5	73.77
NEFL	P07196	73.66
ANKRD24	Q8TF21	70.30
BRF1	Q92994	70.22
PEX6	Q13608	69.87
ESPN	B1AK53	68.76
CBY3	A6NI87	68.59
CEP78	Q5JTW2	64.28
TMIE	Q8NEW7	63.41
TCF19	Q9Y242	63.17
OXR1	Q8N573	60.31
FOXI1	Q12951	60.03
USP31	Q70CQ4	58.39
FOXF2	Q12947	58.04
COL11A1	P12107	53.06
COL11A2	P13942	50.18
PKHD1L1	Q86WI1
TENM1	Q9UKZ4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 218. Enrichment computed across 75 evidence-associated genes (55 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 55 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	7	25.9×	2e-06	ESPN, CDH23, TMC1, TMIE, MYO15A, MYO3A, MYO7A
Sensory processing of sound by inner hair cells of the cochlea	7	20.8×	4e-06	ESPN, CDH23, TMC1, TMIE, MYO15A, MYO3A, MYO7A
Sensory processing of sound	4	22.4×	0.002	CDH23, MYO15A, MYO3A, MYO7A
tRNA Aminoacylation	4	20.8×	0.002	NARS2, HARS2, KARS1, LARS1
Mitochondrial tRNA aminoacylation	3	28.3×	0.007	NARS2, HARS2, KARS1
MET activates PTK2 signaling	3	20.8×	0.014	COL11A1, COL11A2, HGF
Collagen chain trimerization	3	14.2×	0.038	COL11A1, COL11A2, COL9A1
Translation	5	5.6×	0.051	MRPS7, NARS2, HARS2, KARS1, LARS1
Assembly of collagen fibrils and other multimeric structures	3	10.9×	0.057	COL11A1, COL11A2, COL9A1
Sensory Perception	4	6.9×	0.057	CDH23, MYO15A, MYO3A, MYO7A
Transcriptional and post-translational regulation of MITF-M expression and activity	3	9.7×	0.068	EDN3, KARS1, LARS1
Collagen degradation	3	9.6×	0.068	COL11A1, COL11A2, COL9A1
Collagen biosynthesis and modifying enzymes	3	9.3×	0.068	COL11A1, COL11A2, COL9A1
Defective SLC26A4 causes Pendred syndrome (PDS)	1	207.6×	0.075	SLC26A4
Cytosolic tRNA aminoacylation	2	16.0×	0.100	KARS1, LARS1
Drug-mediated inhibition of MET activation	1	103.8×	0.131	HGF
Mitochondrial transcription initiation	1	69.2×	0.157	TFAM
Oligomerization of connexins into connexons	1	69.2×	0.157	GJB2
Transport of connexins along the secretory pathway	1	69.2×	0.157	GJB2
MET activates STAT3	1	69.2×	0.157	HGF
Catecholamine biosynthesis	1	51.9×	0.190	DBH
Transcription from mitochondrial promoters	1	51.9×	0.190	TFAM
Disinhibition of SNARE formation	1	41.5×	0.194	STX4
Vitamin B1 (thiamin) metabolism	1	41.5×	0.194	SLC19A2
MET activates PTPN11	1	41.5×	0.194	HGF
MET interacts with TNS proteins	1	41.5×	0.194	HGF
Developmental Lineage of Pancreatic Ductal Cells	2	8.3×	0.194	COL11A1, COL11A2
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	34.6×	0.201	SCP2
MET Receptor Activation	1	34.6×	0.201	HGF
MET activates PI3K/AKT signaling	1	34.6×	0.201	HGF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 71 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	20	28.4×	2e-21	STX4, WFS1, ESPN, CDH23, CDC14A, PKHD1L1, COL11A1, COL11A2 (+12 more)
detection of mechanical stimulus involved in sensory perception of sound	3	39.6×	0.014	TMC1, COL11A1, PTPRQ
auditory receptor cell stereocilium organization	3	35.6×	0.014	CDH23, ANKRD24, MYO7A
inner ear morphogenesis	4	16.9×	0.014	COL11A1, TMIE, FOXI1, MYO15A
mitochondrial respiratory chain complex assembly	2	79.1×	0.032	TFAM, AIFM1
equilibrioception	2	67.8×	0.037	CDH23, MYO7A
transepithelial chloride transport	2	52.7×	0.040	SLC12A2, CLCNKA
olfactory behavior	2	52.7×	0.040	WFS1, LMX1A
sensory perception of light stimulus	2	52.7×	0.040	CDH23, MYO7A
locomotory behavior	4	10.1×	0.040	CDH23, DBH, LMX1A, MYO15A
DNA topological change	2	47.5×	0.043	TOP3A, TOP1MT
regulation of pH	2	39.6×	0.057	ATP6V0A4, SLC26A4
positive regulation of leukocyte chemotaxis	2	36.5×	0.062	EDN3, IL6
leukocyte mediated immunity	1	237.3×	0.066	DBH
lysyl-tRNA aminoacylation	1	237.3×	0.066	KARS1
deoxyribonucleoside triphosphate metabolic process	1	237.3×	0.066	RRM2B
microvillar actin bundle assembly	1	237.3×	0.066	ESPN
positive regulation of intracellular cholesterol transport	1	237.3×	0.066	SCP2
geranylgeranyl diphosphate biosynthetic process	1	237.3×	0.066	GGPS1
intermediate filament polymerization or depolymerization	1	237.3×	0.066	NEFL
positive regulation of cell volume	1	237.3×	0.066	SLC12A2
positive regulation of steroid metabolic process	1	237.3×	0.066	SCP2
regulation of eye pigmentation	1	237.3×	0.066	SPNS2
barbed-end actin filament uncapping	1	237.3×	0.066	CARMIL1
pigment granule transport	1	237.3×	0.066	MYO7A
cellular response to glutathione	1	237.3×	0.066	AFG3L2
regulation of protein polyubiquitination	1	237.3×	0.066	FOXF2
response to D-galactosamine	1	237.3×	0.066	MT-CYB
regulation of vascular associated smooth muscle cell proliferation	1	237.3×	0.066	DBH
membrane protein proteolysis	2	29.7×	0.066	AFG3L2, RET

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
Methotrexate	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Dexamethasone, Prednisolone, Prednisone, Syrup, Valganciclovir.

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 13 · Phased (≥1): 14 · Undrugged: 61

Druggability breadth: 31 of 75 evidence-associated genes (41%) 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
HCRTR1	SUVOREXANT
SLC12A2	BUMETANIDE
MYH14	TUCATINIB
GABRA1	DIAZEPAM
GGPS1	MINODRONIC ACID
GJB2	KANAMYCIN
IL6	PREDNISOLONE
KARS1	IMATINIB
KCNE1	AMBRISENTAN
MYO3A	AXITINIB
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
GABRA1	60	4
KCNE1	14	4
HCRTR1	13	4
MYO3A	9	4
GGPS1	4	4
IL6	3	4
SLC12A2	1	4
SLC19A2	1	2
RRM2B	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUVOREXANT	4	HCRTR1
NALFURAFINE	4	HCRTR1
LEMBOREXANT	4	HCRTR1
DARIDOREXANT	4	HCRTR1
NALFURAFINE HYDROCHLORIDE	4	HCRTR1
BUMETANIDE	4	SLC12A2
TUCATINIB	4	MYH14
DIAZEPAM	4	GABRA1
FLUNITRAZEPAM	4	GABRA1
ESZOPICLONE	4	GABRA1
FLUMAZENIL	4	GABRA1
TRIAZOLAM	4	GABRA1
ALPRAZOLAM	4	GABRA1
ETOMIDATE	4	GABRA1
ZOLPIDEM	4	GABRA1
ENZALUTAMIDE	4	GABRA1
LIOTHYRONINE	4	GABRA1
GANAXOLONE	4	GABRA1
BREXANOLONE	4	GABRA1
APALUTAMIDE	4	GABRA1
CLONAZEPAM	4	GABRA1
LINDANE	4	GABRA1
CHLORDIAZEPOXIDE	4	GABRA1
PROPOFOL	4	GABRA1
ZALEPLON	4	GABRA1
STIRIPENTOL	4	GABRA1
ZURANOLONE	4	GABRA1
CANDESARTAN CILEXETIL	4	GABRA1
SIMVASTATIN	4	GABRA1
EPINASTINE	4	GABRA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 16.

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

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
GABRA1	842	Binding:701, Functional:124, ADMET:13, Toxicity:4
HCRTR1	280	Binding:154, Functional:126
GGPS1	129	Binding:128, ADMET:1
KCNE1	117	Functional:63, Binding:47, ADMET:6, Toxicity:1
MYO3A	82	Binding:82
RRM2B	47	Binding:44, Functional:3
KARS1	46	Binding:45, ADMET:1
SLC26A4	37	Binding:37
LARS1	35	Binding:32, ADMET:2, Functional:1
CDC14A	19	Binding:18, ADMET:1
IL6	16	Binding:16
SLC12A2	13	Binding:9, Functional:4
DBH	7	Binding:6, Functional:1
GJB2	5	Binding:5
SCP2	4	Binding:4
HGF	4	Binding:4
MRPS7	3	Binding:3
SPNS2	3	Binding:3
AFG3L2	3	Binding:3
PTPRR	3	Binding:3
OXR1	2	Binding:2
SLC19A2	2	Functional:1, Binding:1
AIFM1	2	Binding:2
BRF1	1	Binding:1
TFAM	1	Binding:1
WFS1	1	Binding:1
MYH14	1	Binding:1
MYO15A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SCP2	2.3.1.176	propanoyl-CoA C-acyltransferase
PLSCR4	7.6.2.1	P-type phospholipid transporter
RRM2B	1.17.4.1	ribonucleoside-diphosphate reductase
NARS2	6.1.1.22	asparagine-tRNA ligase
DBH	1.14.17.1	dopamine beta-monooxygenase
TOP1MT	5.6.2.1	DNA topoisomerase
AFG3L2	3.4.24.B18
GGPS1	2.5.1.29	geranylgeranyl diphosphate synthase
HARS2	6.1.1.21	histidine-tRNA ligase
KARS1	6.1.1.6	lysine-tRNA ligase
LARS1	6.1.1.4	leucine-tRNA ligase
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)
PEX6	3.6.4.7	peroxisome-assembly ATPase
PTPRQ	3.1.3.48	protein-tyrosine-phosphatase
PTPRR	3.1.3.48	protein-tyrosine-phosphatase
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HCRTR1	280
GABRA1	842
GGPS1	129
KCNE1	117
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 73; 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)
SUVOREXANT	4	HCRTR1
NALFURAFINE	4	HCRTR1
LEMBOREXANT	4	HCRTR1
DARIDOREXANT	4	HCRTR1
NALFURAFINE HYDROCHLORIDE	4	HCRTR1
BUMETANIDE	4	SLC12A2
TUCATINIB	4	MYH14
DIAZEPAM	4	GABRA1
FLUNITRAZEPAM	4	GABRA1
ESZOPICLONE	4	GABRA1
FLUMAZENIL	4	GABRA1
TRIAZOLAM	4	GABRA1
ALPRAZOLAM	4	GABRA1
ETOMIDATE	4	GABRA1
ZOLPIDEM	4	GABRA1
ENZALUTAMIDE	4	GABRA1
LIOTHYRONINE	4	GABRA1
GANAXOLONE	4	GABRA1
BREXANOLONE	4	GABRA1
APALUTAMIDE	4	GABRA1
CLONAZEPAM	4	GABRA1
LINDANE	4	GABRA1
CHLORDIAZEPOXIDE	4	GABRA1
PROPOFOL	4	GABRA1
ZALEPLON	4	GABRA1
STIRIPENTOL	4	GABRA1
ZURANOLONE	4	GABRA1
CANDESARTAN CILEXETIL	4	GABRA1
SIMVASTATIN	4	GABRA1
EPINASTINE	4	GABRA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	HCRTR1, SLC12A2, MYH14, GABRA1, GGPS1, GJB2, IL6, KARS1, KCNE1, MYO3A (+1 more)
B	Phased (≥1) drug, not yet approved	3	SLC19A2, RRM2B, DBH
C	Druggable family + PDB, no drug	10	SCP2, PLSCR4, CTDSP2, SPNS2, AFG3L2, HGF, LARS1, AIFM1, PTPRQ, PTPRR
D	Druggable family + AlphaFold only, no drug	9	PKHD1L1, CDC14A, USP48, USP31, NARS2, TOP1MT, HARS2, SLC26A4, PEX6
E	Difficult family or no structure, no drug	42	OXR1, THOC1, ANKRD24, FOXF2, STX4, BRF1, TCF19, TFAM, TOP3A, WFS1 (+32 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OXR1	2	HCRTR1
WFS1	1	GJB2
ESPN	0	GJB2
TMIE	0	GJB2
FOXI1	0	GJB2
LARS1	35	KARS1
MYO15A	1	GJB2
SLC26A4	37	GJB2
THOC1	0	—
PKHD1L1	0	—
ANKRD24	0	—
FOXF2	0	—
SCP2	4	—
STX4	0	—
BRF1	1	—
TCF19	0	—
TFAM	1	—
TOP3A	0	—
ZSCAN10	0	—
CDH23	0	—
MRPS7	3	—
PLSCR4	0	—
TMC1	0	—
CTDSP2	0	—
CDC14A	19	—
GIPC3	0	—
USP48	0	—
POGZ	0	—
USP31	0	—
CLCNKA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 89.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	67
PHASE1/PHASE2	8
PHASE2	5
PHASE3	3
EARLY_PHASE1	3
PHASE2/PHASE3	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT04733950	Not specified	RECRUITING	Cochlear Implanted Listening Effort and Hearing Attention
NCT05107466	Not specified	RECRUITING	Quantification of Visually Evoked Cortical Potentials in Individuals With Hearing Loss
NCT05402969	Not specified	RECRUITING	Evaluation of Electrode-modiolus Distance and Cochlear Fibrosis Using Depth Sounding and Spectroscopy Tools
NCT05634356	Not specified	RECRUITING	Social Influences on Sensorimotor Integration of Speech Production and Perception During Early Vocal Learning
NCT05670158	Not specified	RECRUITING	Immunity After Cochlear Implantation and Perilymph Molecular Profiles in Sensorineural Hearing Loss
NCT06053190	Not specified	RECRUITING	Effects of Clear Speech on Listening Effort and Memory in Sentence Processing
NCT06226558	Not specified	RECRUITING	Long-Term Outcomes of Children With Congenital CMV in New York State
NCT06229717	Not specified	RECRUITING	Vestibular and Postural Function in an Unselected Group of Children With Sensorineural Hearing Loss
NCT06434129	Not specified	RECRUITING	Role of Diffusion Tensor-magnetic Resonance Imaging in Investigating Sensorineural Hearing Loss
NCT06495268	Not specified	ACTIVE_NOT_RECRUITING	Healthy heaAring for Healthy Ageing: Data-driven Hearing Rehabilitation Intervention to Promote Healthy Hearing
NCT06507007	Not specified	RECRUITING	Genetic and Epigenetic Background of Inner Ear Dysfunction in Turner Syndrome
NCT06699797	Not specified	ACTIVE_NOT_RECRUITING	Pivotal Clinical Trial Evaluating the Safety and Efficacy of the Fully Implanted Acclaim Cochlear Implant
NCT06746038	Not specified	NOT_YET_RECRUITING	Evaluation of Extended Wear Hearing Aid for Mild Hearing Loss
NCT06936449	Not specified	RECRUITING	Long-term Follow-up of a Cochlear Implant With Dexamethasone Eluting Electrode Array
NCT07023250	Not specified	NOT_YET_RECRUITING	Sensorineural Hearing Loss Imprint
NCT07039435	Not specified	RECRUITING	Perceptual Adaptation Following Cochlear Implantation (Aim 3a)
NCT07081542	Not specified	NOT_YET_RECRUITING	Comparative Analysis of Hearing Outcomes: Robotic vs. Manual Insertion of Cochlear Implants
NCT07146841	Not specified	RECRUITING	Hearing Preservation in Cochlear Implantation Surgery

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VALGANCICLOVIR	4	3
ANAKINRA	4	1
DEFERIPRONE	4	1
GINKGO	4	1
SITAGLIPTIN	4	1
DISUFENTON SODIUM	3	1
SYRUP	3	1
RECOMBINANT METHIONYL HUMAN BRAIN-DERIVED NEUROTROPHIC FACTOR	1	1
CHEMBL5220618	0	1
GASTRODIN	0	1