Inherited retinal dystrophy

Summary

Inherited retinal dystrophy (MONDO:0019118) is a disease (an umbrella term covering 105 Mondo subtypes) caused by variants in CLN3, UBAP1L, and IMPG1, with 75 cohort genes (6 GWAS associations across 4 studies) and 39 clinical trials. The dominant Reactome pathway is Cilium Assembly (18 cohort genes). Top therapeutic interventions include minocycline, disulfiram, and metformin.

At a glance

• Causal genes: CLN3 (GenCC Definitive), UBAP1L (GenCC Definitive), IMPG1 (GenCC Strong)
• Umbrella term: 105 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 6
• ClinVar variants: 10,714
• Clinical trials: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inherited retinal dystrophy
Mondo ID	MONDO:0019118
MeSH	D058499
Orphanet	71862
DOID	DOID:8500, DOID:8501
ICD-10-CM	H35.5
NCIT	C35194, C35625
SNOMED CT	314407005, 41799005
UMLS	C0854723
MedGen	208903
GARD	0018916
MedDRA	10038857
Is cancer (heuristic)	no

Also known as: familial retinal dystrophy · fundus dystrophy · genetic retinal dystrophy · hereditary retinal degeneration · hereditary retinal dystrophy · inherited retinal dystrophy · retinal dystrophy

Data availability: 10,714 ClinVar variants · 2 ClinGen variant curations · 6 GWAS associations (4 studies) · 9 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 105 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy

Related subtypes (5): peripheral retinal degeneration, macular degeneration, retinoschisis, cone dystrophy 5, X-linked, cone dystrophy 1, X-linked

Subtypes (105): retinal dystrophies primarily involving Bruch’s membrane, vitreoretinal dystrophy, dystrophies primarily involving the retinal pigment epithelium, retinal dystrophy in systemic or cerebroretinal lipidoses, age-related macular degeneration, helicoid peripapillary chorioretinal degeneration, Sorsby fundus dystrophy, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, pigmented paravenous retinochoroidal atrophy, retinoschisis, autosomal dominant, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, amaurosis-hypertrichosis syndrome, familial benign flecked retina, microcephaly and chorioretinopathy 1, ornithine aminotransferase deficiency, retinal degeneration-nanophthalmos-glaucoma syndrome, retinoschisis of fovea, Revesz syndrome, choroideremia, choroideremia-deafness-obesity syndrome, X-linked retinal dysplasia, X-linked retinoschisis, progressive bifocal chorioretinal atrophy, aceruloplasminemia, late-onset retinal degeneration, infantile cerebellar-retinal degeneration, progressive retinal dystrophy due to retinol transport defect, microcornea-myopic chorioretinal atrophy, retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies, macular degeneration, early-onset, cone-rod dystrophy, ectopia lentis-chorioretinal dystrophy-myopia syndrome, foveal hypoplasia-presenile cataract syndrome, MRCS syndrome, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, Leber congenital amaurosis, oligocone trichromacy, Oguchi disease, retinitis pigmentosa, hereditary macular dystrophy, RPE65-related recessive retinopathy, RPGR-related retinopathy, AIPL1-related retinopathy, RP2-related retinopathy, RDH5-related retinopathy, RLBP1-related retinopathy, LCA5-related retinopathy, ATF6-related retinopathy, RAB28-related retinopathy, FLVCR1-related retinopathy with or without ataxia, RPE65-related dominant retinopathy, GUCY2D retinopathy, PDE6A-related retinopathy, ELOVL4-related maculopathy, MAK-related retinopathy, KIZ-related retinopathy, TOPORS-related retinopathy, PRPF8-related retinopathy, RD3-related retinopathy, BEST1-related dominant retinopathy, BEST1-related recessive retinopathy, IMPG2-related recessive retinopathy, IMPG2-related dominant retinopathy, CACNA1F-related retinopathy, CACNA2D4-related retinopathy, CDHR1-related retinopathy, GUCA1A-related retinopathy, RHO-related retinopathy, SNRNP200-related dominant retinopathy, RDH12-related recessive retinopathy, RDH12-related dominant retinopathy, NMNAT1-related retinopathy, CNGA3-related retinopathy, EYS-related retinopathy, GNAT2-related retinopathy, IDH3B-related retinopathy, MERTK-related retinopathy, PRPF31-related retinopathy, GPR179-related retinopathy, GRM6-related retinopathy, ADAM9-related retinopathy, RP1-related recessive retinopathy, RP1-related dominant retinopathy, CERKL-related retinopathy, TRPM1-related retinopathy, CNGB1-related retinopathy, PCARE-related retinopathy, CNGA1-related retinopathy, ABCA4-related retinopathy, NYX-related retinopathy, retinal dystrophy, X-linked, Gardner-Hardcastle type, PDE6C-related retinopathy, PDE6G-related retinopathy, LRIT3-related retinopathy, IMPG1-related dominant retinopathy, IMPG1-related recessive retinopathy, TTLL5-related retinopathy, HGSNAT-related retinopathy, IMPDH1-related retinopathy, PRPH2-related retinopathy, PROM1-related retinopathy, KCNV2-related retinopathy, CRX-related retinopathy, REEP6-related retinopathy, SPATA7-related retinopathy

Genetics & variants

GWAS landscape

6 GWAS associations across 4 studies. Top hits map to 5 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs117628897	9e-13	MYLK	G	3.21
rs972337942	2e-12	RPL21P41 - KBTBD8	C	3.96
rs551148158	7e-12	TMCC1	A	1.88
rs190795661	3e-11	HNRNPA1P57 - LDHAP3	T	2.19
rs141386637	3e-11	NPHP3-ACAD11, ACAD11, ACKR4	G	2.13
rs79103986	3e-11	Y_RNA - LUZP2	A	3.77

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477644	Verma A	2024	1,913	445,867	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480053	Verma A	2024	469	120,614	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481906	Verma A	2024	469	120,614	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435971	Zhou W	2018	83	396,859	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	5

MAF distribution

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

Functional consequences

Consequence	Count
intron_variant	4
intergenic_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs117628897	3	123862829	G>A	0	intron_variant	MYLK	9e-13	Tier 4: intronic/intergenic
rs972337942	3	66893005	C>T	0	intron_variant	RPL21P41 - KBTBD8	2e-12	Tier 4: intronic/intergenic
rs551148158	3	129818476	A>T	0.002	intron_variant	TMCC1	7e-12	Tier 4: intronic/intergenic
rs190795661	2	41281899	T>C	0.001	intergenic_variant	HNRNPA1P57 - LDHAP3	3e-11	Tier 4: intronic/intergenic
rs141386637	3	132600966	G>A	0	missense_variant	NPHP3-ACAD11, ACAD11, ACKR4	3e-11	Tier 1: coding
rs79103986	11	24495484	A>C	0	intron_variant	Y_RNA - LUZP2	3e-11	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

213 uncertain significance, 131 likely benign, 69 conflicting classifications of pathogenicity, 59 benign, 42 pathogenic, 40 pathogenic/likely pathogenic, 33 benign/likely benign, 13 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048172	NM_000350.3(ABCA4):c.5311G>A (p.Gly1771Arg)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066342	NM_000350.3(ABCA4):c.4225A>G (p.Ile1409Val)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067804	NM_000350.3(ABCA4):c.4670A>G (p.Tyr1557Cys)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069499	NM_000350.3(ABCA4):c.2069del (p.Gly690fs)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1184970	NM_000350.3(ABCA4):c.3287C>T (p.Ser1096Leu)	ABCA4	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
1069711	NM_032119.4(ADGRV1):c.18025C>T (p.Arg6009Ter)	ADGRV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175346	NM_001378454.1(ALMS1):c.8598del (p.Glu2867fs)	ALMS1	Pathogenic	no assertion criteria provided
1151	NM_152618.3(BBS12):c.1115_1116del (p.Gly371_Phe372insTer)	BBS12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069894	NM_004183.4(BEST1):c.72G>A (p.Trp24Ter)	BEST1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075268	NM_145200.5(CABP4):c.370del (p.Arg124fs)	CABP4	Pathogenic	criteria provided, single submitter
11615	NM_001256789.3(CACNA1F):c.2872C>T (p.Arg958Ter)	CACNA1F	Pathogenic	criteria provided, multiple submitters, no conflicts
1071354	NM_001793.6(CDH3):c.1519C>T (p.Gln507Ter)	CDH3	Pathogenic	criteria provided, single submitter
1019831	NM_000330.4(RS1):c.311A>C (p.Asn104Thr)	CDKL5	Pathogenic	criteria provided, single submitter
1171013	NM_001330691.3(CEP78):c.1459-1G>T	CEP78	Pathogenic	criteria provided, single submitter
1171014	NM_001330691.3(CEP78):c.449T>C (p.Leu150Ser)	CEP78	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1205787	NM_201548.5(CERKL):c.453G>A (p.Trp151Ter)	CERKL	Pathogenic	criteria provided, multiple submitters, no conflicts
1073121	NM_000390.4(CHM):c.817C>T (p.Gln273Ter)	CHM	Pathogenic	criteria provided, multiple submitters, no conflicts
1075258	NM_000390.4(CHM):c.616dup (p.Thr206fs)	CHM	Pathogenic	criteria provided, single submitter
11149	NM_000390.4(CHM):c.1484C>A (p.Ser495Ter)	CHM	Pathogenic	criteria provided, multiple submitters, no conflicts
11152	NM_000390.4(CHM):c.1584_1587del (p.Val529fs)	CHM	Pathogenic	criteria provided, multiple submitters, no conflicts
11154	NM_000390.4(CHM):c.877C>T (p.Arg293Ter)	CHM	Pathogenic	criteria provided, multiple submitters, no conflicts
1064924	NM_006383.4(CIB2):c.196C>T (p.Arg66Trp)	CIB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1056891	NM_001298.3(CNGA3):c.1537G>A (p.Gly513Arg)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1071996	NM_001298.3(CNGA3):c.542A>G (p.Tyr181Cys)	CNGA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1074017	NM_001297.5(CNGB1):c.1684del (p.Ala562fs)	CNGB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066344	NM_201253.3(CRB1):c.2105A>G (p.Tyr702Cys)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066707	NM_201253.3(CRB1):c.652+3_652+6del	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068031	NM_201253.3(CRB1):c.1349G>A (p.Cys450Tyr)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066963	NM_001142800.2(EYS):c.5836-1G>C	EYS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 60 · Orphanet: 146 · 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
CLN3	Definitive	Autosomal recessive	inherited retinal dystrophy	7
IMPG1	Definitive	Autosomal dominant	vitelliform macular dystrophy 4	7
PRPH2	Definitive	Autosomal dominant	hereditary macular dystrophy	21
UBAP1L	Definitive	Autosomal recessive	inherited retinal dystrophy	3
SEMA4A	Moderate	Autosomal recessive	inherited retinal dystrophy	7
ADAMTS18	Limited	Autosomal recessive	inherited retinal dystrophy	6
ASRGL1	Limited	Autosomal recessive	inherited retinal dystrophy
C19orf44	Limited	Autosomal recessive	inherited retinal dystrophy
SIX6	Limited	Autosomal recessive	inherited retinal dystrophy	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEMA4A	Orphanet:1872	Cone rod dystrophy
SEMA4A	Orphanet:440437	Familial colorectal cancer Type X
SEMA4A	Orphanet:791	Retinitis pigmentosa
ADAMTS18	Orphanet:369970	Microcornea-myopic chorioretinal atrophy-telecanthus syndrome
CLN3	Orphanet:699780	Juvenile CLN3 disease
CLN3	Orphanet:699796	Protracted juvenile CLN3 disease
IMPG1	Orphanet:251287	Benign concentric annular macular dystrophy
IMPG1	Orphanet:791	Retinitis pigmentosa
IMPG1	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:227796	Fundus albipunctatus
PRPH2	Orphanet:52427	Retinitis punctata albescens
PRPH2	Orphanet:75377	Central areolar choroidal dystrophy
PRPH2	Orphanet:791	Retinitis pigmentosa
PRPH2	Orphanet:827	Stargardt disease
PRPH2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PRPH2	Orphanet:99003	Multifocal pattern dystrophy simulating fundus flavimaculatus
SIX6	Orphanet:35612	Nanophthalmos
SIX6	Orphanet:435930	Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome
SIX6	Orphanet:98938	Colobomatous microphthalmia
UBAP1L	Orphanet:1872	Cone rod dystrophy
RGS9	Orphanet:75374	Bradyopsia
RHO	Orphanet:215	Congenital stationary night blindness
RHO	Orphanet:52427	Retinitis punctata albescens
RHO	Orphanet:791	Retinitis pigmentosa
GRK1	Orphanet:75382	Oguchi disease
RLBP1	Orphanet:227796	Fundus albipunctatus
RLBP1	Orphanet:52427	Retinitis punctata albescens
RLBP1	Orphanet:791	Retinitis pigmentosa
RLBP1	Orphanet:85128	Bothnia retinal dystrophy
ROM1	Orphanet:791	Retinitis pigmentosa
RP1	Orphanet:791	Retinitis pigmentosa
RP2	Orphanet:791	Retinitis pigmentosa
RP9	Orphanet:791	Retinitis pigmentosa
RPE65	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
RPE65	Orphanet:65	Leber congenital amaurosis
RPE65	Orphanet:791	Retinitis pigmentosa
RPGR	Orphanet:1872	Cone rod dystrophy
RPGR	Orphanet:244	Primary ciliary dyskinesia
RPGR	Orphanet:247522	Primary ciliary dyskinesia-retinitis pigmentosa syndrome
RPGR	Orphanet:49382	Achromatopsia
RPGR	Orphanet:791	Retinitis pigmentosa
RS1	Orphanet:792	X-linked retinoschisis
CNNM4	Orphanet:1873	Jalili syndrome
SAG	Orphanet:75382	Oguchi disease
SAG	Orphanet:791	Retinitis pigmentosa
CWC27	Orphanet:166035	Brachydactyly-short stature-retinitis pigmentosa syndrome
SEMA6B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SGSH	Orphanet:79269	Sanfilippo syndrome type A

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
SEMA4A	HGNC:10729	ENSG00000196189	Q9H3S1	Semaphorin-4A	gencc,clinvar
ASRGL1	HGNC:16448	ENSG00000162174	Q7L266	Isoaspartyl peptidase/L-asparaginase	gencc,clinvar
ADAMTS18	HGNC:17110	ENSG00000140873	Q8TE60	A disintegrin and metalloproteinase with thrombospondin motifs 18	gencc,clinvar
CLN3	HGNC:2074	ENSG00000188603	Q13286	Battenin	gencc,clinvar
IMPG1	HGNC:6055	ENSG00000112706	Q17R60	Interphotoreceptor matrix proteoglycan 1	gencc,clinvar
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	gencc,clinvar
SIX6	HGNC:10892	ENSG00000184302	O95475	Homeobox protein SIX6	gencc
C19orf44	HGNC:26141	ENSG00000105072	Q9H6X5	Uncharacterized protein C19orf44	gencc
UBAP1L	HGNC:40028	ENSG00000246922	F5GYI3	Ubiquitin-associated protein 1-like	gencc
RGS9	HGNC:10004	ENSG00000108370	O75916	Regulator of G-protein signaling 9	clinvar
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar
GRK1	HGNC:10013	ENSG00000185974	Q15835	Rhodopsin kinase GRK1	clinvar
RLBP1	HGNC:10024	ENSG00000140522	P12271	Retinaldehyde-binding protein 1	clinvar
RNF7	HGNC:10070	ENSG00000114125	Q9UBF6	RING-box protein 2	clinvar
ROM1	HGNC:10254	ENSG00000149489	Q03395	Rod outer segment membrane protein 1	clinvar
RP1	HGNC:10263	ENSG00000104237	P56715	Oxygen-regulated protein 1	clinvar
RP2	HGNC:10274	ENSG00000102218	O75695	Protein XRP2	clinvar
RP9	HGNC:10288	ENSG00000164610	Q8TA86	Retinitis pigmentosa 9 protein	clinvar
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	clinvar
RPGR	HGNC:10295	ENSG00000156313	Q92834	X-linked retinitis pigmentosa GTPase regulator	clinvar
RS1	HGNC:10457	ENSG00000102104	O15537	Retinoschisin	clinvar
CNNM4	HGNC:105	ENSG00000158158	Q6P4Q7	Metal transporter CNNM4	clinvar
SAG	HGNC:10521	ENSG00000130561	P10523	S-arrestin	clinvar
CWC27	HGNC:10664	ENSG00000153015	Q6UX04	Spliceosome-associated protein CWC27 homolog	clinvar
SEMA6B	HGNC:10739	ENSG00000167680	Q9H3T3	Semaphorin-6B	clinvar
SGSH	HGNC:10818	ENSG00000181523	P51688	N-sulphoglucosamine sulphohydrolase	clinvar
SLC24A1	HGNC:10975	ENSG00000074621	O60721	Sodium/potassium/calcium exchanger 1	clinvar
SLC4A7	HGNC:11033	ENSG00000033867	Q9Y6M7	Sodium bicarbonate cotransporter 3	clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
SPP2	HGNC:11256	ENSG00000072080	Q13103	Secreted phosphoprotein 24	clinvar
PLK4	HGNC:11397	ENSG00000142731	O00444	Serine/threonine-protein kinase PLK4	clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
SYN3	HGNC:11496	ENSG00000185666	O14994	Synapsin-3	clinvar
TEAD1	HGNC:11714	ENSG00000187079	P28347	Transcriptional enhancer factor TEF-1	clinvar
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	clinvar
TIMP3	HGNC:11822	ENSG00000100234	P35625	Metalloproteinase inhibitor 3	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
GIGYF2	HGNC:11960	ENSG00000204120	Q6Y7W6	GRB10-interacting GYF protein 2	clinvar
TUB	HGNC:12406	ENSG00000166402	P50607	Tubby protein homolog	clinvar
TULP1	HGNC:12423	ENSG00000112041	O00294	Tubby-related protein 1	clinvar
USH1C	HGNC:12597	ENSG00000006611	Q9Y6N9	Harmonin	clinvar
CFAP410	HGNC:1260	ENSG00000160226	O43822	Cilia- and flagella-associated protein 410	clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar
CLRN1	HGNC:12605	ENSG00000163646	P58418	Clarin-1	clinvar
BEST1	HGNC:12703	ENSG00000167995	O76090	Bestrophin-1	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
YME1L1	HGNC:12843	ENSG00000136758	Q96TA2	ATP-dependent zinc metalloprotease YME1L1	clinvar
SCAPER	HGNC:13081	ENSG00000140386	Q9BY12	S phase cyclin A-associated protein in the endoplasmic reticulum	clinvar
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	clinvar
ARL6	HGNC:13210	ENSG00000113966	Q9H0F7	ADP-ribosylation factor-like protein 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEMA4A	Semaphorin-4A	Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling.
ASRGL1	Isoaspartyl peptidase/L-asparaginase	Has both L-asparaginase and beta-aspartyl peptidase activity.
CLN3	Battenin	Mediates microtubule-dependent, anterograde transport connecting the Golgi network, endosomes, autophagosomes, lysosomes and plasma membrane, and participates in several cellular processes such as regulation of lysosomal pH, lysosome prote…
IMPG1	Interphotoreceptor matrix proteoglycan 1	Chondroitin sulfate-, heparin- and hyaluronan-binding protein.
PRPH2	Peripherin-2	Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure.
SIX6	Homeobox protein SIX6	May be involved in eye development.
RGS9	Regulator of G-protein signaling 9	Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form.
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.
GRK1	Rhodopsin kinase GRK1	Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade.
RLBP1	Retinaldehyde-binding protein 1	Soluble retinoid carrier essential the proper function of both rod and cone photoreceptors.
RNF7	RING-box protein 2	Catalytic component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes), which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
ROM1	Rod outer segment membrane protein 1	Plays a role in rod outer segment (ROS) morphogenesis.
RP1	Oxygen-regulated protein 1	Microtubule-associated protein regulating the stability and length of the microtubule-based axoneme of photoreceptors.
RP2	Protein XRP2	Acts as a GTPase-activating protein (GAP) involved in trafficking between the Golgi and the ciliary membrane.
RP9	Retinitis pigmentosa 9 protein	Is thought to be a target protein for the PIM1 kinase.
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
RPGR	X-linked retinitis pigmentosa GTPase regulator	Acts as a guanine-nucleotide releasing factor (GEF) for RAB8A and RAB37 by promoting the conversion of inactive RAB-GDP to the active form RAB-GTP.
RS1	Retinoschisin	Binds negatively charged membrane lipids, such as phosphatidylserine and phosphoinositides.
CNNM4	Metal transporter CNNM4	Probable metal transporter.
SAG	S-arrestin	Binds to photoactivated, phosphorylated RHO and terminates RHO signaling via G-proteins by competing with G-proteins for the same binding site on RHO.
CWC27	Spliceosome-associated protein CWC27 homolog	As part of the spliceosome, plays a role in pre-mRNA splicing.
SEMA6B	Semaphorin-6B	Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance.
SGSH	N-sulphoglucosamine sulphohydrolase	Catalyzes a step in lysosomal heparan sulfate degradation.
SLC24A1	Sodium/potassium/calcium exchanger 1	Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
SLC4A7	Sodium bicarbonate cotransporter 3	Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	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.
SPP2	Secreted phosphoprotein 24	Could coordinate an aspect of bone turnover.
PLK4	Serine/threonine-protein kinase PLK4	Serine/threonine-protein kinase that plays a central role in centriole duplication.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
SYN3	Synapsin-3	May be involved in the regulation of neurotransmitter release and synaptogenesis.
TEAD1	Transcriptional enhancer factor TEF-1	Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis.
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
TIMP3	Metalloproteinase inhibitor 3	Mediates a variety of processes including matrix regulation and turnover, inflammation, and angiogenesis, through reversible inhibition of zinc protease superfamily enzymes, primarily matrix metalloproteinases (MMPs).
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
GIGYF2	GRB10-interacting GYF protein 2	Key component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation.
TUB	Tubby protein homolog	Functions in signal transduction from heterotrimeric G protein-coupled receptors.
TULP1	Tubby-related protein 1	Required for normal development of photoreceptor synapses.
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.
CFAP410	Cilia- and flagella-associated protein 410	Plays a role in cilia formation and/or maintenance.
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.
BEST1	Bestrophin-1	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).
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.
YME1L1	ATP-dependent zinc metalloprotease YME1L1	ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region.
SCAPER	S phase cyclin A-associated protein in the endoplasmic reticulum	CCNA2/CDK2 regulatory protein that transiently maintains CCNA2 in the cytoplasm.
C3	Complement C3	Precursor of non-enzymatic components of the classical, alternative, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adapt…
ARL6	ADP-ribosylation factor-like protein 6	Involved in membrane protein trafficking at the base of the ciliary organelle.
ESPN	Espin	Multifunctional actin-bundling protein.
RPGRIP1	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	May function as scaffolding protein.
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.

Protein-family classification

Druggable: 22 · Difficult: 9 · Unknown: 44 · Druggable fraction: 0.29

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
Protease	5	2.4×	0.651
Complement	1	3.6×	0.829
Ion channel	1	1.5×	0.829
Scaffold/PPI	5	1.1×	0.829
Enzyme (other)	7	1.1×	0.829
Phosphatase	1	1.1×	0.829
Kinase	3	1.1×	0.829
Other/Unknown	44	1.1×	0.829
Transporter	1	1.0×	0.829
GPCR	2	0.6×	0.985
Transcription factor	4	0.4×	0.985
Antibody/Immunoglobulin	1	0.4×	0.985

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEMA4A	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf
ASRGL1	Protease	yes	3.4.19.5	Peptidase_T2, Ntn_hydrolases_N, ASRGL1_meta
ADAMTS18	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
CLN3	Transporter	yes		Battenin_disease_Cln3, Battenin_disease_Cln3_subgr, MFS_trans_sf
IMPG1	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS
SIX6	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
C19orf44	Other/Unknown	no		DUF4614, C19orf44-like
UBAP1L	Other/Unknown	no		UMA, UBAP1, UBAP1_C
RGS9	Other/Unknown	no		DEP_dom, G-protein_gamma-like_dom, RGS
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin
GRK1	Kinase	yes	2.7.11.14	GPCR_kinase, Prot_kinase_dom, AGC-kinase_C
RLBP1	Other/Unknown	no		CRAL-TRIO_dom, CRAL/TRIO_N_dom, CRAL/TRIO_N_dom_sf
RNF7	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_H2
ROM1	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS
RP1	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
RP2	Other/Unknown	no		CARP_motif, Tubulin-bd_cofactor_C_dom, CAP/MinC_C
RP9	Other/Unknown	no		PAP-1
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase
RPGR	Other/Unknown	no		Reg_chr_condens, RCC1/BLIP-II, Signaling_Regulatory_Domain
RS1	Other/Unknown	no		FA58C, Galactose-bd-like_sf, Neuropilin_MCO_CoagFactor
CNNM4	Enzyme (other)	yes	7.2.2.14	cNMP-bd_dom, CBS_dom, CNNM
SAG	Other/Unknown	no		Arrestin, Arrestin-like_N, Arrestin-like_C
CWC27	Enzyme (other)	yes	5.2.1.8	Cyclophilin-type_PPIase_dom, Cyclophilin-type_PPIase_CS, Cyclophilin-like_dom_sf
SEMA6B	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf
SGSH	Phosphatase	yes	3.10.1.1	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
SLC24A1	Other/Unknown	no		K/Na/Ca-exchanger, SLC24A1, NaCa_Exmemb
SLC4A7	Other/Unknown	no		HCO3_transpt_euk, HCO3_transpt-like_TM_dom, Band3_cytoplasmic_dom
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
SPP2	Other/Unknown	no		Spp-24, Cystatin_sf
PLK4	Kinase	yes	2.7.11.21	Prot_kinase_dom, POLO_box_dom, Tyr_kinase_AS
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SYN3	Other/Unknown	no		Synapsin, ATP_grasp_subdomain_1, PreATP-grasp_dom_sf
TEAD1	Other/Unknown	no		TEA/ATTS_dom, TEF_metazoa, TEA/ATTS_sf
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
TIMP3	Other/Unknown	no		Netrin_domain, TIMP, TIMP-like_OB-fold
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
GIGYF2	Other/Unknown	no		GYF, GYF-like_dom_sf, GRB10-interact_GYF
TUB	Other/Unknown	no		Tubby_C, Tubby_N, Tubby_C_CS
TULP1	Other/Unknown	no		Tubby_C, Tubby_C_CS, Tubby-like_C
USH1C	Scaffold/PPI	no		PDZ, Harmonin_N, PDZ_sf
CFAP410	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom
CLRN1	Other/Unknown	no		Clarin
BEST1	Other/Unknown	no		Bestrophin, Bestrophin-like
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
YME1L1	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
SCAPER	Transcription factor	no		Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_type, SCAPER_N
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
ARL6	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF

Expression context

Cohort genes with no expression data: 0.

71 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	13
primordial germ cell in gonad	8
right uterine tube	7
sperm	6
ventricular zone	6
mucosa of transverse colon	5
secondary oocyte	4
granulocyte	4
pigmented layer of retina	4
oocyte	4
rectum	4
sural nerve	4
right lobe of liver	4
cortical plate	4
monocyte	3
male germ cell	3
cerebellar hemisphere	3
right hemisphere of cerebellum	3
retina	3
left adrenal gland cortex	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEMA4A	219	broad	marker	monocyte, mononuclear cell, leukocyte
ASRGL1	252	ubiquitous	marker	sperm, male germ cell, right uterine tube
ADAMTS18	152	broad	marker	cerebellar vermis, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
CLN3	134	ubiquitous	marker	mucosa of transverse colon, placenta, granulocyte
IMPG1	155	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, nucleus accumbens, secondary oocyte
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle
SIX6	34	tissue_specific	marker	adenohypophysis, pituitary gland, cranial nerve II
C19orf44	166	ubiquitous	marker	oviduct epithelium, sperm, right uterine tube
UBAP1L	171	tissue_specific	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
RGS9	178	ubiquitous	marker	putamen, caudate nucleus, islet of Langerhans
RHO	38	tissue_specific	marker	optic choroid, neuron projection bundle connecting eye with brain, diaphragm
GRK1	52	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, right lobe of thyroid gland, left lobe of thyroid gland
RLBP1	126	tissue_specific	marker	pigmented layer of retina, retina, optic choroid
RNF7	292	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland
ROM1	201	broad	marker	primordial germ cell in gonad, C1 segment of cervical spinal cord, spinal cord
RP1	103	tissue_specific	marker	right uterine tube, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis
RP2	242	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
RP9	256	ubiquitous	marker	oocyte, left ventricle myocardium, hindlimb stylopod muscle
RPE65	92	tissue_specific	marker	pigmented layer of retina, retina, male germ line stem cell (sensu Vertebrata) in testis
RPGR	281	ubiquitous	marker	sperm, bronchial epithelial cell, right uterine tube
RS1	34	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, oocyte, secondary oocyte
CNNM4	189	ubiquitous	marker	mucosa of transverse colon, rectum, ileal mucosa
SAG	106	tissue_specific	marker	nucleus accumbens, male germ line stem cell (sensu Vertebrata) in testis, left testis
CWC27	253	ubiquitous	marker	tendon of biceps brachii, medial globus pallidus, globus pallidus
SEMA6B	177	ubiquitous	marker	right frontal lobe, anterior cingulate cortex, cingulate cortex
SGSH	272	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, adrenal cortex
SLC24A1	220	ubiquitous	marker	endothelial cell, sural nerve, male germ line stem cell (sensu Vertebrata) in testis
SLC4A7	284	ubiquitous	marker	oocyte, duodenum, calcaneal tendon
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
SPP2	75	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 76.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCT2	7,097
ACO2	4,776
YME1L1	4,274
SPG7	3,970
PLK4	3,694
RHO	3,578
PRPF31	3,427
WFS1	3,409
MED12	3,322
C3	3,199

Intra-cohort edges

A	B	Sources
ADAMTS18	USH2A	string_interaction
ARL6	CCT2	biogrid_interaction
BEST1	ELOVL4	string_interaction
BEST1	IMPG1	string_interaction
BEST1	PRPF31	string_interaction
BEST1	PRPH2	string_interaction
BEST1	RLBP1	string_interaction
BEST1	RPE65	string_interaction
BEST1	RPGR	string_interaction
CA4	PRPF31	string_interaction
CA4	RP9	string_interaction
CABP4	CACNA1F	biogrid_interaction, string_interaction
CABP4	SLC24A1	string_interaction
CACNA1F	RPGR	string_interaction
CACNA1F	RS1	string_interaction
CCT2	RPE65	biogrid_interaction, intact
CDH23	CLRN1	string_interaction
CDH23	ESPN	string_interaction
CDH23	PCDH15	string_interaction
CDH23	USH1C	biogrid_interaction, intact
CDH23	USH2A	string_interaction
CDHR1	PRPH2	string_interaction
CDHR1	RPGRIP1	string_interaction
CDHR1	SEMA4A	string_interaction
CDKL5	RS1	string_interaction
CLN3	SGSH	string_interaction
CLRN1	PCDH15	string_interaction
CLRN1	USH2A	string_interaction
ELOVL4	IMPG1	string_interaction
ELOVL4	PRPH2	string_interaction
GRK1	RHO	biogrid_interaction, string_interaction
GRK1	SAG	string_interaction
IMPG1	NBAS	string_interaction
IMPG1	PRPH2	string_interaction
KLHL7	PRPF31	string_interaction
KLHL7	RP9	string_interaction
NBAS	SCAPER	string_interaction
PCDH15	USH2A	string_interaction
PNPLA6	SPG7	string_interaction
PRPF31	PRPF6	biogrid_interaction, intact, string_interaction
PRPF31	PRPH2	string_interaction
PRPF31	RP9	string_interaction
PRPF31	RPGR	string_interaction
PRPF6	RP9	string_interaction
PRPH2	RHO	string_interaction
PRPH2	RLBP1	string_interaction
PRPH2	ROM1	string_interaction
PRPH2	RP1L1	string_interaction
PRPH2	RP9	string_interaction
PRPH2	RPGR	string_interaction

Structural data

PDB: 42 · AlphaFold-only: 33 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75
CCT2	P78371	65
PRPF6	O94906	33
PRPF31	Q8WWY3	30
PLK4	O00444	19
BEST1	O76090	19
ASRGL1	Q7L266	15
TEAD1	P28347	14
USH1C	Q9Y6N9	11
CA4	P22748	10
CWC27	Q6UX04	9
PCDH15	Q96QU1	8
RNF7	Q9UBF6	7
CDH23	Q9H251	6
RHO	P08100	4
RLBP1	P12271	4
RP2	O75695	3
RPGR	Q92834	3
CDKL5	O76039	3
MED12	Q93074	3
GIGYF2	Q6Y7W6	3
RS1	O15537	2
CNNM4	Q6P4Q7	2
SGSH	P51688	2
TULP1	O00294	2
SCAPER	Q9BY12	2
C1QTNF5	Q9BXJ0	2
PRPH2	P23942	1
GRK1	Q15835	1
ROM1	Q03395	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44
RPE65	Q16518	95.34
CLRN1	P58418	90.74
ABHD12	Q8N2K0	85.60
SAG	P10523	85.44
SEMA4A	Q9H3S1	85.05
ELOVL4	Q9GZR5	84.53
IFT81	Q8WYA0	83.45
CLN3	Q13286	81.81
SIX6	O95475	81.68
RP9	Q8TA86	78.99
CDHR1	Q96JP9	78.79
SEMA6B	Q9H3T3	74.81
NBAS	A2RRP1	74.42
RGS9	O75916	74.35
WFS1	O76024	73.85
ADAMTS18	Q8TE60	73.83
YME1L1	Q96TA2	70.79
ADGRA3	Q8IWK6	70.20
PNPLA6	Q8IY17	69.75
SPP2	Q13103	69.68
ESPN	B1AK53	68.76
CACNA1F	O60840	67.46
UBAP1L	F5GYI3	66.48
CABP4	P57796	65.01
IMPG1	Q17R60	59.26
SLC24A1	O60721	55.56
KIZ	Q2M2Z5	54.82
PRDM13	Q9H4Q3	53.52
C19orf44	Q9H6X5	52.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 434. Enrichment computed across 250 evidence-associated genes (158 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 158 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cilium Assembly	18	12.4×	2e-12	ARL6, CCT2, BBS7, INPP5E, AHI1, CEP78, BBS10, SCLT1 (+10 more)
Anchoring of the basal body to the plasma membrane	16	11.4×	1e-10	PLK4, CEP250, NPHP4, AHI1, TMEM216, OFD1, CEP78, SCLT1 (+8 more)
Inactivation, recovery and regulation of the phototransduction cascade	11	22.1×	2e-10	RGS9, RHO, GRK1, SAG, CNGA1, CNGB1, RGS9BP, GNAT1 (+3 more)
Organelle biogenesis and maintenance	18	7.5×	3e-09	ARL6, CCT2, BBS7, INPP5E, AHI1, CEP78, BBS10, SCLT1 (+10 more)
The canonical retinoid cycle in rods (twilight vision)	8	26.3×	3e-08	RHO, RLBP1, RPE65, RDH12, CYP4V2, ABCA4, LRAT, MYO7A
BBSome-mediated cargo-targeting to cilium	8	25.1×	3e-08	ARL6, CCT2, BBS7, TTC8, BBS10, BBS12, BBS9, MKKS
Activation of the phototransduction cascade	6	36.1×	3e-07	RHO, SAG, SLC24A1, CNGA1, CNGB1, GNAT1
Sensory processing of sound by outer hair cells of the cochlea	9	11.6×	3e-06	USH1C, ESPN, CDH23, PCDH15, USH1G, WHRN, CIB2, FSCN2 (+1 more)
Cargo trafficking to the periciliary membrane	8	12.6×	9e-06	ARL6, CCT2, BBS7, INPP5E, BBS10, BBS12, ARL3, MKKS
Sensory processing of sound by inner hair cells of the cochlea	9	9.3×	2e-05	USH1C, ESPN, CDH23, PCDH15, USH1G, WHRN, CIB2, FSCN2 (+1 more)
Recruitment of mitotic centrosome proteins and complexes	9	7.7×	9e-05	PLK4, TUBGCP6, CEP250, OFD1, CEP78, CEP290, CEP164, ALMS1 (+1 more)
Loss of Nlp from mitotic centrosomes	8	8.0×	2e-04	PLK4, CEP250, OFD1, CEP78, CEP290, CEP164, ALMS1, NEK2
Loss of proteins required for interphase microtubule organization from the centrosome	8	8.0×	2e-04	PLK4, CEP250, OFD1, CEP78, CEP290, CEP164, ALMS1, NEK2
AURKA Activation by TPX2	8	7.7×	3e-04	PLK4, CEP250, OFD1, CEP78, CEP290, CEP164, ALMS1, NEK2
Recruitment of NuMA to mitotic centrosomes	9	6.6×	3e-04	PLK4, TUBGCP6, CEP250, OFD1, CEP78, CEP290, CEP164, ALMS1 (+1 more)
Intraflagellar transport	7	8.9×	3e-04	IFT81, WDR19, IFT74, DYNC2I2, IFT140, DYNC2H1, IFT172
Trafficking of myristoylated proteins to the cilium	3	43.4×	7e-04	RP2, ARL3, NPHP3
Visual phototransduction	6	9.9×	7e-04	RPE65, SAG, SLC24A1, ABCA4, LRAT, MYO7A
Regulation of PLK1 Activity at G2/M Transition	8	6.4×	8e-04	PLK4, CEP250, OFD1, CEP78, CEP290, CEP164, ALMS1, NEK2
Hedgehog ‘off’ state	6	6.8×	0.005	WDR19, OFD1, IFT140, DYNC2H1, IFT172, MKS1
Centrosome maturation	5	8.0×	0.008	CEP78, CEP290, CEP164, ALMS1, NEK2
Retinoid cycle disease events	2	36.1×	0.020	ABCA4, LRAT
Diseases associated with visual transduction	2	36.1×	0.020	ABCA4, LRAT
Diseases of the neuronal system	2	36.1×	0.020	ABCA4, LRAT
Sensory Perception	7	4.2×	0.024	RPE65, SAG, SLC24A1, CDH23, ABCA4, LRAT, MYO7A
Processing of SMDT1	3	12.1×	0.030	SPG7, YME1L1, PMPCA
Citric acid cycle (TCA cycle)	3	8.0×	0.096	ACO2, IDH3A, IDH3B
The phototransduction cascade	2	16.1×	0.096	SAG, SLC24A1
Signaling by RNF43 mutants	2	16.1×	0.096	FZD4, LRP5
MET activates PTK2 signaling	3	7.2×	0.110	COL11A1, COL2A1, LAMA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 239 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
visual perception	72	23.9×	1e-78	IMPG1, PRPH2, RGS9, RHO, GRK1, RLBP1, ROM1, RP1 (+64 more)
photoreceptor cell maintenance	30	45.0×	7e-42	RHO, RP1, TUB, TULP1, USH1C, USH2A, CLRN1, CDH23 (+22 more)
detection of light stimulus involved in visual perception	17	46.1×	2e-23	PRPH2, ROM1, RPE65, TULP1, BEST1, CACNA1F, CEP250, CACNA2D4 (+9 more)
cilium assembly	34	10.5×	2e-22	RP2, RPGR, PLK4, CFAP410, ARL6, IFT81, WDR19, CEP250 (+26 more)
retina development in camera-type eye	19	20.3×	8e-18	PRPH2, RP1, TUB, TULP1, SCAPER, RP1L1, MFRP, NPHP4 (+11 more)
photoreceptor cell outer segment organization	12	52.9×	2e-17	PRPH2, ROM1, RP1, CDHR1, RP1L1, NPHP4, CNGB1, AHI1 (+4 more)
sensory perception of light stimulus	9	70.5×	3e-15	USH1C, USH2A, CLRN1, CDH23, PCDH15, USH1G, WHRN, ADGRV1 (+1 more)
non-motile cilium assembly	16	19.4×	1e-14	RPGRIP1, CEP250, BBS7, TTC8, IFT74, TMEM216, BBS10, CEP290 (+8 more)
eye photoreceptor cell development	9	31.7×	4e-10	RPGR, TULP1, MFRP, POC5, CEP290, FSCN2, GNAT1, MYO7A (+1 more)
intraciliary transport	10	23.5×	7e-10	RPGR, TUB, IFT81, BBS12, WDPCP, DYNC2I2, IFT172, LCA5 (+2 more)
equilibrioception	6	60.4×	6e-09	USH1C, CLRN1, CDH23, PCDH15, USH1G, MYO7A
sensory perception of sound	17	7.2×	2e-08	TUB, USH1C, USH2A, CLRN1, WFS1, ESPN, CDH23, PCDH15 (+9 more)
retina homeostasis	7	32.9×	5e-08	RPE65, TULP1, WHRN, CDH3, CNGB1, POC1B, AIPL1
protein localization to photoreceptor outer segment	5	50.4×	9e-07	ROM1, TUB, TULP1, SPATA7, PCARE
protein localization to cilium	8	13.4×	9e-06	TUB, TULP1, ARL6, CEP78, IFT140, DYNC2H1, BBS9, ARL3
G protein-coupled opsin signaling pathway	4	56.4×	1e-05	RHO, GRK1, SAG, GNAT1
maintenance of animal organ identity	4	56.4×	1e-05	USH2A, ADGRV1, IQCB1, NPHP3
inner ear receptor cell differentiation	4	56.4×	1e-05	USH2A, WHRN, ADGRV1, PDZD7
Norrin signaling pathway	4	56.4×	1e-05	TSPAN12, FZD4, LRP5, NDP
inner ear receptor cell stereocilium organization	6	21.1×	1e-05	USH1C, USH1G, WHRN, ADGRV1, TTC8, MKS1
determination of left/right symmetry	9	9.6×	2e-05	ARL6, BBS7, IFT74, IFT140, CC2D2A, DYNC2H1, MKKS, MKS1 (+1 more)
phototransduction	7	14.5×	2e-05	RHO, CABP4, CNGB1, GNAT2, GUCA1A, GUCA1B, NR2E3
visual behavior	4	47.0×	3e-05	NPHP4, GNAT1, GNAT2, NPHP1
photoreceptor cell morphogenesis	4	47.0×	3e-05	CABP4, CDHR1, TMEM216, CFAP418
phototransduction, visible light	5	27.1×	3e-05	RHO, RP1, ABCA4, AIPL1, GNAT1
retinal blood vessel morphogenesis	4	40.3×	6e-05	FZD4, LAMA1, LRP5, NDP
retina layer formation	6	16.3×	6e-05	RS1, ARL6, TSPAN12, TOPORS, CRB1, NDP
detection of mechanical stimulus involved in sensory perception of sound	5	19.6×	2e-04	WHRN, ADGRV1, COL11A1, PDZD7, MKKS
retinal rod cell differentiation	4	31.3×	2e-04	BBS10, GNAT1, GNAT2, NDP
smoothened signaling pathway	9	6.8×	3e-04	CFAP410, BBS7, KIAA0586, CTNNA1, WDPCP, CC2D2A, IFT172, ARL3 (+1 more)

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 7 · Phased (≥1): 13 · Undrugged: 62

Druggability breadth: 75 of 250 evidence-associated genes (30%) 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
GRK1	RUXOLITINIB
PLK4	MOMELOTINIB
CDKL5	FEDRATINIB
CA4	METHAZOLAMIDE
CACNA1F	BEPRIDIL
ABHD12	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLK4	65	4
CA4	59	4
CACNA1F	48	4
CDKL5	14	4
GRK1	12	4
ABHD12	2	4
CWC27	1	2
TEAD1	1	2
TIMP3	1	3
MED12	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RUXOLITINIB	4	GRK1, PLK4
NINTEDANIB	4	GRK1, PLK4
SUNITINIB	4	CACNA1F, GRK1, PLK4
MIDOSTAURIN	4	GRK1, PLK4
MOMELOTINIB	4	PLK4
FEDRATINIB	4	CDKL5, PLK4
AXITINIB	4	PLK4
SORAFENIB	4	PLK4
ENTRECTINIB	4	PLK4
DABRAFENIB	4	PLK4
FOSTAMATINIB	4	PLK4
CERITINIB	4	PLK4
VANDETANIB	4	PLK4
GILTERITINIB	4	PLK4
PAZOPANIB	4	PLK4
DASATINIB	4	CACNA1F, PLK4
ERLOTINIB	4	PLK4
CRIZOTINIB	4	PLK4
IMATINIB	4	CA4, PLK4
CAPMATINIB	4	CDKL5
METHAZOLAMIDE	4	CA4
ACETAZOLAMIDE	4	CA4
ZONISAMIDE	4	CA4
TRICHLORMETHIAZIDE	4	CA4
CHLORTHALIDONE	4	CA4
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	CA4
ACETAMINOPHEN	4	CA4
POTASSIUM IODIDE	4	CA4
CELECOXIB	4	CA4
PYRITHIONE ZINC	4	CA4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 16.

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

Symbol	Assays	Type breakdown
PLK4	303	Binding:293, Functional:10
CACNA1F	221	Binding:135, Functional:79, Toxicity:5, ADMET:2
CA4	202	Binding:195, ADMET:6, Functional:1
GRK1	123	Binding:123
TEAD1	85	Binding:82, Functional:3
CDKL5	74	Binding:74
ABHD12	35	Binding:31, Toxicity:3, ADMET:1
C3	15	Binding:15
PCDH15	9	Binding:9
PRPF6	8	Binding:8
CCT2	8	Binding:8
CWC27	7	Binding:7
MED12	6	Binding:6
PRPF31	6	Binding:6
GIGYF2	5	Binding:5
ADGRA3	2	Binding:2
RHO	1	Binding:1
RP1	1	Binding:1
SLC4A7	1	Binding:1
TIMP3	1	Binding:1
CFAP410	1	Binding:1
WFS1	1	Binding:1
PRDM13	1	Binding:1
ELOVL4	1	Binding:1
NBAS	1	Binding:1
KLHL7	1	Binding:1
PANK2	1	Binding:1
PNPLA6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASRGL1	3.4.19.5, 3.5.1.1	beta-aspartyl-peptidase, asparaginase
GRK1	2.7.11.14	rhodopsin kinase
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase
CNNM4	7.2.2.14	P-type Mg2+ transporter
CWC27	5.2.1.8	peptidylprolyl isomerase
SGSH	3.10.1.1	N-sulfoglucosamine sulfohydrolase
SPG7	3.4.24.B18
PLK4	2.7.11.21	polo kinase
CDKL5	2.7.11.22	cyclin-dependent kinase
ACO2	4.2.1.3	aconitate hydratase
YME1L1	3.4.24.B18
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase
CA4	4.2.1.1	carbonic anhydrase
CAPN5	3.4.22.B25
PANK2	2.7.1.33	pantothenate kinase
CCT2	3.6.4.B10

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GRK1	123
PLK4	303
CA4	202
CACNA1F	221

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)
RUXOLITINIB	4	GRK1, PLK4
NINTEDANIB	4	GRK1, PLK4
SUNITINIB	4	CACNA1F, GRK1, PLK4
MIDOSTAURIN	4	GRK1, PLK4
MOMELOTINIB	4	PLK4
FEDRATINIB	4	CDKL5, PLK4
AXITINIB	4	PLK4
SORAFENIB	4	PLK4
ENTRECTINIB	4	PLK4
DABRAFENIB	4	PLK4
FOSTAMATINIB	4	PLK4
CERITINIB	4	PLK4
VANDETANIB	4	PLK4
GILTERITINIB	4	PLK4
PAZOPANIB	4	PLK4
DASATINIB	4	CACNA1F, PLK4
ERLOTINIB	4	PLK4
CRIZOTINIB	4	PLK4
IMATINIB	4	CA4, PLK4
CAPMATINIB	4	CDKL5
METHAZOLAMIDE	4	CA4
ACETAZOLAMIDE	4	CA4
ZONISAMIDE	4	CA4
TRICHLORMETHIAZIDE	4	CA4
CHLORTHALIDONE	4	CA4
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	CA4
ACETAMINOPHEN	4	CA4
POTASSIUM IODIDE	4	CA4
CELECOXIB	4	CA4
PYRITHIONE ZINC	4	CA4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	GRK1, PLK4, CDKL5, CA4, CACNA1F, ABHD12
B	Phased (≥1) drug, not yet approved	7	CWC27, TEAD1, TIMP3, MED12, PRPF31, PRPF6, CCT2
C	Druggable family + PDB, no drug	8	ASRGL1, RHO, CNNM4, SGSH, SPG7, C3, CAPN5, PANK2
D	Druggable family + AlphaFold only, no drug	7	ADAMTS18, CLN3, RPE65, ACO2, USH2A, YME1L1, ADGRA3
E	Difficult family or no structure, no drug	47	SEMA4A, IMPG1, PRPH2, SIX6, C19orf44, UBAP1L, RGS9, RLBP1, RNF7, ROM1 (+37 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RHO	1	GRK1
RP9	0	PRPF31
RS1	0	CDKL5
SAG	0	GRK1
CABP4	0	CACNA1F
KLHL7	1	PRPF31
SEMA4A	0	—
ASRGL1	0	—
ADAMTS18	0	—
CLN3	0	—
IMPG1	0	—
PRPH2	0	—
SIX6	0	—
C19orf44	0	—
UBAP1L	0	—
RGS9	0	—
RLBP1	0	—
RNF7	0	—
ROM1	0	—
RP1	1	—
RP2	0	—
RPE65	0	—
RPGR	0	—
CNNM4	0	—
SEMA6B	0	—
SGSH	0	—
SLC24A1	0	—
SLC4A7	1	—
SPG7	0	—
SPP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 39.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	23
PHASE1/PHASE2	6
PHASE2	3
PHASE1	3
PHASE3	2
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)
NCT06375239	Not specified	RECRUITING	Observational Study to Assess Endpoint Operational Feasibility & Measurement Properties in Patients with Retinal Degeneration
NCT06908161	Not specified	NOT_YET_RECRUITING	Functional Assessments in Vision Impairment
NCT07085533	Not specified	RECRUITING	Natural History Study of Inherited Retinal Diseases
NCT07502664	Not specified	RECRUITING	Development and Evaluation of Functional Visual Field and Navigation Endpoints in Moderate to Profound Inherited Retinal Disease (DEFINE-IRD)
NCT07529041	Not specified	ENROLLING_BY_INVITATION	Real-time Acoustic Biofeedback for Enhancing Fixation Stability: A Proof-of-concept Study to Improve Ophthalmic Imaging Diagnostic Quality
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MINOCYCLINE	4	2
DISULFIRAM	4	1
METFORMIN	4	1
BRINRETIGENE VESGEDPARVOVEC	2	1
SEPOFARSEN	2	1
CHEMBL5417591	0	1