Cone-rod dystrophy

Summary

Cone-rod dystrophy (MONDO:0015993) is a disease (an umbrella term covering 28 Mondo subtypes) caused by variants in GUCY2D and UBAP1L, with 75 cohort genes and 11 clinical trials. The dominant Reactome pathway is The canonical retinoid cycle in rods (twilight vision) (6 cohort genes). Top therapeutic interventions include cholesterol.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal genes: GUCY2D (GenCC Definitive), UBAP1L (GenCC Strong)
• Umbrella term: 28 Mondo subtypes
• Cohort genes: 75
• ClinVar variants: 319
• Phenotypes (HPO): 15
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.5	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000613	Photophobia	Very frequent (80-99%)
HP:0000662	Nyctalopia	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)
HP:0000529	Progressive visual loss	Frequent (30-79%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000551	Color vision defect	Frequent (30-79%)
HP:0000603	Central scotoma	Frequent (30-79%)
HP:0001105	Retinal atrophy	Frequent (30-79%)
HP:0007641	Dyschromatopsia	Frequent (30-79%)
HP:0007737	Bone spicule pigmentation of the retina	Frequent (30-79%)
HP:0007843	Attenuation of retinal blood vessels	Frequent (30-79%)
HP:0030466	Abnormal full-field electroretinogram	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0012508	Metamorphopsia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cone-rod dystrophy
Mondo ID	MONDO:0015993
MeSH	D000071700
OMIM	120970
Orphanet	1872
DOID	DOID:0050572
UMLS	C4085590
MedGen	896366
GARD	0010790
Is cancer (heuristic)	no

Also known as: CRD

Data availability: 319 ClinVar variants · 34 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 28 Mondo subtypes.

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

Related subtypes (104): 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, 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

Subtypes (28): cone-rod dystrophy 2, macular degeneration, X-linked atrophic, cone-rod dystrophy 1, cone-rod dystrophy 5, cone-rod dystrophy 6, cone dystrophy 3, cone-rod dystrophy 7, cone-rod dystrophy 3, Leber congenital amaurosis 4, cone-rod dystrophy 8, Newfoundland cone-rod dystrophy, cone-rod dystrophy 13, cone-rod dystrophy 10, cone-rod dystrophy 11, retinal cone dystrophy 4, cone-rod dystrophy 12, cone-rod dystrophy 9, cone-rod dystrophy 15, cone-rod dystrophy 16, cone-rod dystrophy 17, cone-rod dystrophy 18, cone-rod dystrophy 19, cone-rod dystrophy 20, cone-rod dystrophy 21, X-linked cone-rod dystrophy, cone-rod dystrophy 22, cone-rod dystrophy 14, cone-rod dystrophy 24

Genetics & variants

GWAS landscape

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

Variant details and genetic-evidence tiers

ClinVar germline variants

319 retrieved; paginated sample, class counts are floors:

73 pathogenic, 72 conflicting classifications of pathogenicity, 71 uncertain significance, 42 pathogenic/likely pathogenic, 27 benign, 16 benign/likely benign, 15 likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
438483	NM_022787.3(NMNAT1):c.[53A>G];[769G>A]		Pathogenic	no assertion criteria provided
1460063	NM_000350.3(ABCA4):c.4720G>T (p.Glu1574Ter)	ABCA4	Pathogenic	reviewed by expert panel
236096	NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
236102	NM_000350.3(ABCA4):c.3482G>A (p.Arg1161His)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236128	NM_000350.3(ABCA4):c.5312+1G>A	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
3544480	NM_000350.3(ABCA4):c.5714+1G>C	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
438100	NM_000350.3(ABCA4):c.5196+1137G>A	ABCA4	Pathogenic	reviewed by expert panel
635987	NM_000350.3(ABCA4):c.5528_5533del (p.Arg1843_Gly1844del)	ABCA4	Pathogenic	criteria provided, single submitter
813134	NM_000350.3(ABCA4):c.346_347del (p.Ala116fs)	ABCA4	Pathogenic	criteria provided, single submitter
813136	NM_000350.3(ABCA4):c.4269C>T (p.Gly1423=)	ABCA4	Pathogenic	criteria provided, single submitter
813143	NM_000350.3(ABCA4):c.639del (p.Phe213fs)	ABCA4	Pathogenic	criteria provided, single submitter
92869	NM_000350.3(ABCA4):c.4540-2A>G	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
99208	NM_000350.3(ABCA4):c.3212C>T (p.Ser1071Leu)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
99217	NM_000350.3(ABCA4):c.32T>C (p.Leu11Pro)	ABCA4	Pathogenic	reviewed by expert panel
99284	NM_000350.3(ABCA4):c.4462T>C (p.Cys1488Arg)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99292	NM_000350.3(ABCA4):c.4537dup (p.Gln1513fs)	ABCA4	Pathogenic	reviewed by expert panel
99321	NM_000350.3(ABCA4):c.4793C>A (p.Ala1598Asp)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99340	NM_000350.3(ABCA4):c.5044_5058del (p.Val1682_Val1686del)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
99403	NM_000350.3(ABCA4):c.5714+5G>A	ABCA4	Pathogenic	reviewed by expert panel
1708172	NM_003816.3(ADAM9):c.1616del (p.Cys539fs)	ADAM9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804635	NM_003816.3(ADAM9):c.17_18del (p.Arg6fs)	ADAM9	Pathogenic	no assertion criteria provided
6878	NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter)	ADAM9	Pathogenic	criteria provided, single submitter
6879	NM_003816.3(ADAM9):c.411-8A>G	ADAM9	Pathogenic	no assertion criteria provided
812214	NM_003816.3(ADAM9):c.1455C>A (p.Tyr485Ter)	ADAM9	Pathogenic	no assertion criteria provided
812221	NM_001378454.1(ALMS1):c.805C>T (p.Arg269Ter)	ALMS1	Pathogenic	criteria provided, multiple submitters, no conflicts
190959	NM_145200.5(CABP4):c.646C>T (p.Arg216Ter)	CABP4	Pathogenic	criteria provided, multiple submitters, no conflicts
195237	NM_001256789.3(CACNA1F):c.244C>T (p.Arg82Ter)	CACNA1F	Pathogenic	criteria provided, multiple submitters, no conflicts
438129	NM_001256789.3(CACNA1F):c.946TTC[2] (p.Phe318del)	CACNA1F	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587382	NM_001256789.3(CACNA1F):c.4471C>T (p.Arg1491Ter)	CACNA1F	Pathogenic	criteria provided, multiple submitters, no conflicts
812251	NM_001256789.3(CACNA1F):c.1015-2A>G	CACNA1F	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 202 · Orphanet: 157 · 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
ABCA4	Definitive	Autosomal recessive	severe early-childhood-onset retinal dystrophy	12
ADAM9	Definitive	Autosomal recessive	cone-rod dystrophy 9	6
CDHR1	Definitive	Autosomal recessive	cone-rod dystrophy 15	5
CRX	Definitive	Autosomal dominant	cone-rod dystrophy 2	10
GUCA1A	Definitive	Autosomal dominant	cone-rod dystrophy 14	8
GUCY2D	Definitive	Autosomal dominant	cone-rod dystrophy	12
OPN1LW	Definitive	X-linked	blue cone monochromacy	5
OPN1MW	Definitive	X-linked	blue cone monochromacy	6
POC1B	Definitive	Autosomal recessive	cone-rod dystrophy 20	6
PROM1	Definitive	Autosomal dominant	retinal macular dystrophy type 2	10
PRPH2	Definitive	Autosomal dominant	hereditary macular dystrophy	21
RAB28	Definitive	Autosomal recessive	cone-rod dystrophy 18	5
RPGRIP1	Definitive	Autosomal recessive	cone-rod dystrophy 13	6
TTLL5	Definitive	Autosomal recessive	cone-rod dystrophy 19	5
UBAP1L	Definitive	Autosomal recessive	inherited retinal dystrophy	3
CACNA1F	Strong	X-linked	X-linked cone-rod dystrophy 3	7
CACNA2D4	Strong	Autosomal recessive	retinal cone dystrophy 4	4
DRAM2	Strong	Autosomal recessive	cone-rod dystrophy 21	4
PITPNM3	Strong	Autosomal dominant	cone-rod dystrophy 5	3
RAX2	Strong	Autosomal dominant	cone-rod dystrophy 11	9
RIMS1	Strong	Autosomal dominant	cone-rod dystrophy 7	7
TLCD3B	Strong	Autosomal recessive	cone-rod dystrophy 22	2
SEMA4A	Moderate	Autosomal recessive	inherited retinal dystrophy	7
UNC119	Moderate	Autosomal dominant	cone-rod dystrophy 24	5
ATF6	Supportive	Autosomal dominant	cone-rod dystrophy	6
CFAP410	Supportive	Autosomal dominant	cone-rod dystrophy	4
CNGA3	Supportive	Autosomal dominant	cone-rod dystrophy	5
NMNAT1	Supportive	Autosomal dominant	cone-rod dystrophy	6
RPGR	Supportive	Autosomal dominant	cone-rod dystrophy	10
GPR45	Limited	Autosomal recessive	cone-rod dystrophy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SEMA4A	Orphanet:1872	Cone rod dystrophy
SEMA4A	Orphanet:440437	Familial colorectal cancer Type X
SEMA4A	Orphanet:791	Retinitis pigmentosa
UNC119	Orphanet:1872	Cone rod dystrophy
UNC119	Orphanet:228000	Idiopathic CD4 lymphocytopenia
CFAP410	Orphanet:1872	Cone rod dystrophy
CFAP410	Orphanet:653709	Cone rod dystrophy-short stature syndrome
CFAP410	Orphanet:803	Amyotrophic lateral sclerosis
RPGRIP1	Orphanet:1872	Cone rod dystrophy
RPGRIP1	Orphanet:564	Meckel syndrome
RPGRIP1	Orphanet:65	Leber congenital amaurosis
CACNA1F	Orphanet:178333	Åland Islands eye disease
CACNA1F	Orphanet:1872	Cone rod dystrophy
CACNA1F	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
CDHR1	Orphanet:1872	Cone rod dystrophy
CDHR1	Orphanet:791	Retinitis pigmentosa
NMNAT1	Orphanet:1872	Cone rod dystrophy
NMNAT1	Orphanet:65	Leber congenital amaurosis
TTLL5	Orphanet:1872	Cone rod dystrophy
CACNA2D4	Orphanet:1872	Cone rod dystrophy
CACNA2D4	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
CNGA3	Orphanet:1872	Cone rod dystrophy
CNGA3	Orphanet:49382	Achromatopsia
ADAM9	Orphanet:1872	Cone rod dystrophy
CRX	Orphanet:1872	Cone rod dystrophy
CRX	Orphanet:65	Leber congenital amaurosis
CRX	Orphanet:791	Retinitis pigmentosa
DRAM2	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:827	Stargardt disease
GUCA1A	Orphanet:1871	Progressive cone dystrophy
GUCA1A	Orphanet:1872	Cone rod dystrophy
GUCA1A	Orphanet:75377	Central areolar choroidal dystrophy
GUCY2D	Orphanet:1872	Cone rod dystrophy
GUCY2D	Orphanet:65	Leber congenital amaurosis
GUCY2D	Orphanet:75377	Central areolar choroidal dystrophy
PROM1	Orphanet:1872	Cone rod dystrophy
PROM1	Orphanet:319640	Retinal macular dystrophy type 2
PROM1	Orphanet:791	Retinitis pigmentosa
PROM1	Orphanet:827	Stargardt disease
RAB28	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:227796	Fundus albipunctatus
PRPH2	Orphanet:52427	Retinitis punctata albescens

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPGR	HGNC:10295	ENSG00000156313	Q92834	X-linked retinitis pigmentosa GTPase regulator	gencc,clinvar
SEMA4A	HGNC:10729	ENSG00000196189	Q9H3S1	Semaphorin-4A	gencc,clinvar
UNC119	HGNC:12565	ENSG00000109103	Q13432	Protein unc-119 homolog A	gencc,clinvar
CFAP410	HGNC:1260	ENSG00000160226	O43822	Cilia- and flagella-associated protein 410	gencc,clinvar
RPGRIP1	HGNC:13436	ENSG00000092200	Q96KN7	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	gencc,clinvar
CACNA1F	HGNC:1393	ENSG00000102001	O60840	Voltage-dependent L-type calcium channel subunit alpha-1F	gencc,clinvar
CDHR1	HGNC:14550	ENSG00000148600	Q96JP9	Cadherin-related family member 1	gencc,clinvar
NMNAT1	HGNC:17877	ENSG00000173614	Q9HAN9	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	gencc,clinvar
TTLL5	HGNC:19963	ENSG00000119685	Q6EMB2	Tubulin polyglutamylase TTLL5	gencc,clinvar
CACNA2D4	HGNC:20202	ENSG00000151062	Q7Z3S7	Voltage-dependent calcium channel subunit alpha-2/delta-4	gencc,clinvar
CNGA3	HGNC:2150	ENSG00000144191	Q16281	Cyclic nucleotide-gated channel alpha-3	gencc,clinvar
ADAM9	HGNC:216	ENSG00000168615	Q13443	Disintegrin and metalloproteinase domain-containing protein 9	gencc,clinvar
CRX	HGNC:2383	ENSG00000105392	O43186	Cone-rod homeobox protein	gencc,clinvar
DRAM2	HGNC:28769	ENSG00000156171	Q6UX65	DNA damage-regulated autophagy modulator protein 2	gencc,clinvar
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	gencc,clinvar
GUCA1A	HGNC:4678	ENSG00000048545	P43080	Guanylyl cyclase-activating protein 1	gencc,clinvar
GUCY2D	HGNC:4689	ENSG00000132518	Q02846	Retinal guanylyl cyclase 1	gencc,clinvar
PROM1	HGNC:9454	ENSG00000007062	O43490	Prominin-1	gencc,clinvar
RAB28	HGNC:9768	ENSG00000157869	P51157	Ras-related protein Rab-28	gencc,clinvar
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	gencc,clinvar
SLC4A7	HGNC:11033	ENSG00000033867	Q9Y6M7	Sodium bicarbonate cotransporter 3	gencc
RIMS1	HGNC:17282	ENSG00000079841	Q86UR5	Regulating synaptic membrane exocytosis protein 1	gencc
RAX2	HGNC:18286	ENSG00000173976	Q96IS3	Retina and anterior neural fold homeobox protein 2	gencc
PITPNM3	HGNC:21043	ENSG00000091622	Q9BZ71	Membrane-associated phosphatidylinositol transfer protein 3	gencc
TLCD3B	HGNC:25295	ENSG00000149926	Q71RH2	Ceramide synthase	gencc
POC1B	HGNC:30836	ENSG00000139323	Q8TC44	POC1 centriolar protein homolog B	gencc
UBAP1L	HGNC:40028	ENSG00000246922	F5GYI3	Ubiquitin-associated protein 1-like	gencc
OPN1MW	HGNC:4206	ENSG00000268221	P04001	Medium-wave-sensitive opsin 1	gencc
GPR45	HGNC:4503	ENSG00000135973	Q9Y5Y3	Probable G-protein coupled receptor 45	gencc
ATF6	HGNC:791	ENSG00000118217	P18850	Cyclic AMP-dependent transcription factor ATF-6 alpha	gencc
OPN1LW	HGNC:9936	ENSG00000102076	P04000	Long-wave-sensitive opsin 1	gencc
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar
RP1	HGNC:10263	ENSG00000104237	P56715	Oxygen-regulated protein 1	clinvar
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	clinvar
SGSH	HGNC:10818	ENSG00000181523	P51688	N-sulphoglucosamine sulphohydrolase	clinvar
SSBP1	HGNC:11317	ENSG00000106028	Q04837	Single-stranded DNA-binding protein, mitochondrial	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar
ARL6	HGNC:13210	ENSG00000113966	Q9H0F7	ADP-ribosylation factor-like protein 6	clinvar
CDH23	HGNC:13733	ENSG00000107736	Q9H251	Cadherin-23	clinvar
CABP4	HGNC:1386	ENSG00000175544	P57796	Calcium-binding protein 4	clinvar
NLGN3	HGNC:14289	ENSG00000196338	Q9NZ94	Neuroligin-3	clinvar
IFT81	HGNC:14313	ENSG00000122970	Q8WYA0	Intraflagellar transport protein 81 homolog	clinvar
PRPF31	HGNC:15446	ENSG00000105618	Q8WWY3	U4/U6 small nuclear ribonucleoprotein Prp31	clinvar
GPHN	HGNC:15465	ENSG00000171723	Q9NQX3	Gephyrin	clinvar
PANK2	HGNC:15894	ENSG00000125779	Q9BZ23	Pantothenate kinase 2, mitochondrial	clinvar
RP1L1	HGNC:15946	ENSG00000183638	Q8IWN7	Retinitis pigmentosa 1-like 1 protein	clinvar
IMPG2	HGNC:18362	ENSG00000081148	Q9BZV3	Interphotoreceptor matrix proteoglycan 2	clinvar
CUX2	HGNC:19347	ENSG00000111249	O14529	Homeobox protein cut-like 2	clinvar
KCNV2	HGNC:19698	ENSG00000168263	Q8TDN2	Potassium voltage-gated channel subfamily V member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SEMA4A	Semaphorin-4A	Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling.
UNC119	Protein unc-119 homolog A	Involved in synaptic functions in photoreceptor cells, the signal transduction in immune cells as a Src family kinase activator, endosome recycling, the uptake of bacteria and endocytosis, protein trafficking in sensory neurons and as lipi…
CFAP410	Cilia- and flagella-associated protein 410	Plays a role in cilia formation and/or maintenance.
RPGRIP1	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	May function as scaffolding protein.
CACNA1F	Voltage-dependent L-type calcium channel subunit alpha-1F	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CDHR1	Cadherin-related family member 1	Potential calcium-dependent cell-adhesion protein.
NMNAT1	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP.
TTLL5	Tubulin polyglutamylase TTLL5	Polyglutamylase which modifies tubulin, generating polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of tubulin.
CACNA2D4	Voltage-dependent calcium channel subunit alpha-2/delta-4	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
CNGA3	Cyclic nucleotide-gated channel alpha-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
ADAM9	Disintegrin and metalloproteinase domain-containing protein 9	Metalloprotease that cleaves and releases a number of molecules with important roles in tumorigenesis and angiogenesis, such as TEK, KDR, EPHB4, CD40, VCAM1 and CDH5.
CRX	Cone-rod homeobox protein	Transcription factor that binds and transactivates the sequence 5’-TAATC[CA]-3’ which is found upstream of several photoreceptor-specific genes, including the opsin genes.
DRAM2	DNA damage-regulated autophagy modulator protein 2	Plays a role in the initiation of autophagy.
ABCA4	Retinal-specific phospholipid-transporting ATPase ABCA4	Flippase that catalyzes in an ATP-dependent manner the transport of retinal-phosphatidylethanolamine conjugates like 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leafl…
GUCA1A	Guanylyl cyclase-activating protein 1	Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated.
GUCY2D	Retinal guanylyl cyclase 1	Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.
PROM1	Prominin-1	May play a role in cell differentiation, proliferation and apoptosis.
RAB28	Ras-related protein Rab-28	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
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.
SLC4A7	Sodium bicarbonate cotransporter 3	Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry.
RIMS1	Regulating synaptic membrane exocytosis protein 1	Rab effector involved in exocytosis.
RAX2	Retina and anterior neural fold homeobox protein 2	May be involved in modulating the expression of photoreceptor specific genes.
PITPNM3	Membrane-associated phosphatidylinositol transfer protein 3	Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro).
TLCD3B	Ceramide synthase	Involved in ceramide synthesis.
POC1B	POC1 centriolar protein homolog B	Plays an important role in centriole assembly and/or stability and ciliogenesis.
OPN1MW	Medium-wave-sensitive opsin 1	Visual pigments are the light-absorbing molecules that mediate vision.
GPR45	Probable G-protein coupled receptor 45	Orphan receptor.
ATF6	Cyclic AMP-dependent transcription factor ATF-6 alpha	Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 alpha), which is embedded in the endoplasmic reticulum membrane.
OPN1LW	Long-wave-sensitive opsin 1	Visual pigments are the light-absorbing molecules that mediate vision.
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.
RP1	Oxygen-regulated protein 1	Microtubule-associated protein regulating the stability and length of the microtubule-based axoneme of photoreceptors.
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
SGSH	N-sulphoglucosamine sulphohydrolase	Catalyzes a step in lysosomal heparan sulfate degradation.
SSBP1	Single-stranded DNA-binding protein, mitochondrial	Binds preferentially and cooperatively to pyrimidine rich single-stranded DNA (ss-DNA).
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.
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.
ARL6	ADP-ribosylation factor-like protein 6	Involved in membrane protein trafficking at the base of the ciliary organelle.
CDH23	Cadherin-23	Cadherins are calcium-dependent cell adhesion proteins.
CABP4	Calcium-binding protein 4	Involved in normal synaptic function through regulation of Ca(2+) influx and neurotransmitter release in photoreceptor synaptic terminals and in auditory transmission.
NLGN3	Neuroligin-3	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
IFT81	Intraflagellar transport protein 81 homolog	Component of the intraflagellar transport (IFT) complex B: together with IFT74, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium.
PRPF31	U4/U6 small nuclear ribonucleoprotein Prp31	Involved in pre-mRNA splicing as component of the spliceosome.
GPHN	Gephyrin	Microtubule-associated protein involved in membrane protein-cytoskeleton interactions.
PANK2	Pantothenate kinase 2, mitochondrial	Mitochondrial isoform that catalyzes the phosphorylation of pantothenate to generate 4’-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
RP1L1	Retinitis pigmentosa 1-like 1 protein	Required for the differentiation of photoreceptor cells.
IMPG2	Interphotoreceptor matrix proteoglycan 2	Chondroitin sulfate- and hyaluronan-binding proteoglycan involved in the organization of interphotoreceptor matrix; may participate in the maturation and maintenance of the light-sensitive photoreceptor outer segment.
CUX2	Homeobox protein cut-like 2	Transcription factor involved in the control of neuronal proliferation and differentiation in the brain.
KCNV2	Potassium voltage-gated channel subfamily V member 2	Potassium channel subunit.
RDH12	Retinol dehydrogenase 12	Retinoids dehydrogenase/reductase with a clear preference for NADP.

Protein-family classification

Druggable: 23 · Difficult: 8 · Unknown: 44 · Druggable fraction: 0.31

Family distribution

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

Family	Genes	Fold	FDR
Ion channel	5	7.4×	0.006
Transporter	3	3.1×	0.397
GPCR	4	1.3×	0.936
Phosphatase	1	1.1×	0.936
Kinase	3	1.1×	0.936
Other/Unknown	44	1.1×	0.936
Enzyme (other)	5	0.8×	0.936
Transcription factor	6	0.7×	0.936
Protease	1	0.5×	0.936
Scaffold/PPI	2	0.5×	0.936
Antibody/Immunoglobulin	1	0.4×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPGR	Other/Unknown	no		Reg_chr_condens, RCC1/BLIP-II, Signaling_Regulatory_Domain
SEMA4A	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf
UNC119	Other/Unknown	no		PDED_dom, Ig_E-set, PDED_dom_sf
CFAP410	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
RPGRIP1	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
CACNA1F	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, Ion_trans_dom
CDHR1	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
NMNAT1	Enzyme (other)	yes	2.7.7.1	Cyt_trans-like, NadD/NMNAT, Rossmann-like_a/b/a_fold
TTLL5	Other/Unknown	no		TTL/TTLL_fam
CACNA2D4	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
CNGA3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
ADAM9	Protease	yes	3.4.24.B9	EGF, Peptidase_M12B, Disintegrin_dom
CRX	Transcription factor	no		HD, Homeodomain-like_sf, Otx_TF_C
DRAM2	Other/Unknown	no		CWH43_N, DRAM/TMEM150_Autophagy_Mod
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR
GUCA1A	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
GUCY2D	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom
PROM1	Other/Unknown	no		Prominin
RAB28	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS
SLC4A7	Other/Unknown	no		HCO3_transpt_euk, HCO3_transpt-like_TM_dom, Band3_cytoplasmic_dom
RIMS1	Transcription factor	no		C2_dom, PDZ, Rab_BD
RAX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
PITPNM3	Other/Unknown	no		PI_transfer, DDHD_dom, HAD_sf
TLCD3B	Other/Unknown	no		TLC-dom, TLCD
POC1B	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
UBAP1L	Other/Unknown	no		UMA, UBAP1, UBAP1_C
OPN1MW	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin
GPR45	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM, GPC_Orphan_Receptors
ATF6	Transcription factor	no		bZIP, bZIP_sf, ATF_bZIP_TF
OPN1LW	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin
RP1	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase
SGSH	Phosphatase	yes	3.10.1.1	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
SSBP1	Other/Unknown	no		Primosome_PriB/ssb, ssDNA-bd, NA-bd_OB-fold
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom
ARL6	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF
CDH23	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
CABP4	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
NLGN3	Other/Unknown	no		Nlgn, CarbesteraseB, Carboxylesterase_B_CS
IFT81	Other/Unknown	no		IFT81, IFT81_CH, IFT81_N_sf
PRPF31	Other/Unknown	no		Nop_dom, NOSIC, Prp31_C
GPHN	Other/Unknown	no		MoaB/Mog_dom, MoeA_linker/N, MoeA_C_domain_IV
PANK2	Enzyme (other)	yes	2.7.1.33	Type_II_PanK, ATPase_NBD
RP1L1	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
IMPG2	Other/Unknown	no		SEA_dom, EGF, SEA_dom_sf
CUX2	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf
KCNV2	Ion channel	yes		T1-type_BTB, K_chnl_volt-dep_Kv, K_chnl_volt-dep_Kv5/Kv9

Expression context

Cohort genes with no expression data: 1.

66 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)	2
broad (>20)	72
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	14
ventricular zone	8
buccal mucosa cell	8
right uterine tube	6
monocyte	6
sperm	5
granulocyte	5
pigmented layer of retina	5
primordial germ cell in gonad	5
endothelial cell	5
leukocyte	4
left testis	4
right testis	4
islet of Langerhans	4
calcaneal tendon	4
sural nerve	4
bronchial epithelial cell	3
right hemisphere of cerebellum	3
hindlimb stylopod muscle	3
ganglionic eminence	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPGR	281	ubiquitous	marker	sperm, bronchial epithelial cell, right uterine tube
SEMA4A	219	broad	marker	monocyte, mononuclear cell, leukocyte
UNC119	233	ubiquitous	marker	granulocyte, monocyte, mononuclear cell
CFAP410	190	ubiquitous	marker	right uterine tube, adenohypophysis, right frontal lobe
RPGRIP1	168	tissue_specific	marker	left testis, sperm, right testis
CACNA1F	143	tissue_specific	marker	parotid gland, granulocyte, right hemisphere of cerebellum
CDHR1	186	broad	marker	upper arm skin, skin of leg, skin of abdomen
NMNAT1	225	ubiquitous	yes	hindlimb stylopod muscle, muscle of leg, mucosa of transverse colon
TTLL5	288	ubiquitous	marker	left testis, right testis, testis
CACNA2D4	136	broad	yes	monocyte, leukocyte, granulocyte
CNGA3	110	tissue_specific	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence
ADAM9	215	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, gall bladder
CRX	54	tissue_specific	marker	pigmented layer of retina, retina, primordial germ cell in gonad
DRAM2	260	ubiquitous	marker	monocyte, leukocyte, spleen
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
GUCA1A	52	broad	marker	nucleus accumbens, putamen, hypothalamus
GUCY2D	121	tissue_specific	marker	buccal mucosa cell, esophagus mucosa, lower esophagus mucosa
PROM1	252	broad	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
RAB28	284	ubiquitous	marker	tibia, germinal epithelium of ovary, endothelial cell
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle
SLC4A7	284	ubiquitous	marker	oocyte, duodenum, calcaneal tendon
RIMS1	175	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
RAX2	39	tissue_specific	marker	tendon of biceps brachii, buccal mucosa cell, vena cava
PITPNM3	222	broad	marker	pancreatic ductal cell, endothelial cell, Brodmann (1909) area 23
TLCD3B	198	broad	marker	left testis, cortical plate, right testis
POC1B	248	ubiquitous	marker	epithelial cell of pancreas, sperm, corpus callosum
UBAP1L	171	tissue_specific	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
OPN1MW	16		yes	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, sural nerve
GPR45	50		yes	mucosa of urinary bladder, diaphragm, endometrium epithelium
ATF6	283	ubiquitous	marker	corpus epididymis, skin of hip, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 183.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CREBBP	6,959
MECP2	5,688
SSBP1	4,725
SNRNP200	4,118
RHO	3,578
RDH12	3,526
PRPF31	3,427
FAM161A	3,370
MED12	3,322
PROM1	3,302

Intra-cohort edges

A	B	Sources
ABCA4	CDHR1	string_interaction
ABCA4	CERKL	string_interaction
ABCA4	CNGB3	string_interaction
ABCA4	EYS	string_interaction
ABCA4	GUCY2D	string_interaction
ABCA4	IMPG1	string_interaction
ABCA4	IMPG2	string_interaction
ABCA4	KCNV2	string_interaction
ABCA4	PCARE	string_interaction
ABCA4	PITPNM3	string_interaction
ABCA4	PROM1	string_interaction
ABCA4	PRPH2	string_interaction
ABCA4	RAX2	string_interaction
ABCA4	RDH12	string_interaction
ABCA4	RHO	string_interaction
ABCA4	RP1L1	string_interaction
ABCA4	RPE65	string_interaction
ABCA4	RPGR	string_interaction
ABCA4	SEMA4A	string_interaction
ACBD5	CNGA3	biogrid_interaction, intact
ADAM9	PITPNM3	string_interaction
ADAM9	RAX2	string_interaction
ADAM9	RPGRIP1	string_interaction
ALMS1	CEP290	string_interaction
ALMS1	RHO	string_interaction
C10orf105	CDH23	string_interaction
CABP4	CACNA1F	biogrid_interaction, string_interaction
CABP4	CACNA2D4	string_interaction
CACNA1F	CACNA2D4	string_interaction
CACNA1F	OPN1LW	string_interaction
CACNA1F	RPGR	string_interaction
CACNA2D4	KCNV2	string_interaction
CDH23	USH2A	string_interaction
CDHR1	CERKL	string_interaction
CDHR1	GUCY2D	string_interaction
CDHR1	KCNV2	string_interaction
CDHR1	PITPNM3	string_interaction
CDHR1	PROM1	biogrid_interaction, string_interaction
CDHR1	PRPH2	string_interaction
CDHR1	RAB28	string_interaction
CDHR1	RAX2	string_interaction
CDHR1	RIMS1	string_interaction
CDHR1	RPGRIP1	string_interaction
CDHR1	SEMA4A	string_interaction
CDHR1	UNC119	string_interaction
CEP290	CEP78	string_interaction
CEP290	CFAP410	intact
CEP290	RDH12	string_interaction
CEP290	RPGR	string_interaction
CEP290	RPGRIP1	string_interaction

Structural data

PDB: 37 · AlphaFold-only: 37 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CREBBP	Q92793	144
SNRNP200	O75643	81
MERTK	Q12866	42
PRPF31	Q8WWY3	30
CNGA1	P29973	19
ERCC6	P0DP91	12
CNGA3	Q16281	10
UNC119	Q13432	9
CNGB3	Q9NQW8	9
MECP2	P51608	9
ABCA4	P78363	8
NMNAT1	Q9HAN9	6
CDH23	Q9H251	6
SSBP1	Q04837	5
RHO	P08100	4
RPGR	Q92834	3
OPN1MW	P04001	3
MED12	Q93074	3
CUX2	O14529	3
RAB28	P51157	2
SGSH	P51688	2
CFAP410	O43822	1
RPGRIP1	Q96KN7	1
TTLL5	Q6EMB2	1
CRX	O43186	1
PRPH2	P23942	1
SLC4A7	Q9Y6M7	1
RIMS1	Q86UR5	1
PITPNM3	Q9BZ71	1
OPN1LW	P04000	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPE65	Q16518	95.34
RDH12	Q96NR8	92.21
DRAM2	Q6UX65	91.35
TLCD3B	Q71RH2	89.52
PROM1	O43490	85.68
SEMA4A	Q9H3S1	85.05
GPR45	Q9Y5Y3	83.48
IFT81	Q8WYA0	83.45
MFSD8	Q8NHS3	83.20
SCLT1	Q96NL6	82.44
GUCY2D	Q02846	82.37
CLN3	Q13286	81.81
CACNA2D4	Q7Z3S7	81.69
CERKL	Q49MI3	79.82
CDHR1	Q96JP9	78.79
POC1B	Q8TC44	77.62
ADAM9	Q13443	76.14
KCNV2	Q8TDN2	75.55
MAPRE2	Q15555	75.12
RAX2	Q96IS3	71.72
GUCA1A	P43080	71.28
CACNA1F	O60840	67.46
FAM161A	Q3B820	66.83
UBAP1L	F5GYI3	66.48
CABP4	P57796	65.01
CEP78	Q5JTW2	64.28
C10orf105	Q8TEF2	63.46
CEP290	O15078	60.90
IMPG1	Q17R60	59.26
ATF6	P18850	56.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 262. Enrichment computed across 83 evidence-associated genes (49 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 49 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The canonical retinoid cycle in rods (twilight vision)	6	63.6×	8e-08	ABCA4, RHO, RPE65, RDH12, MYO7A, RBP3
Inactivation, recovery and regulation of the phototransduction cascade	5	32.4×	5e-05	GUCA1A, GUCY2D, RHO, CNGA1, PDE6B
The retinoid cycle in cones (daylight vision)	3	99.9×	2e-04	OPN1MW, RBP3, OPN1LW
Opsins	3	77.7×	4e-04	RHO, OPN1MW, OPN1LW
Organelle biogenesis and maintenance	7	9.4×	4e-04	SSBP1, ARL6, CREBBP, CEP78, SCLT1, CEP290, ALMS1
Activation of the phototransduction cascade	3	58.3×	7e-04	RHO, CNGA1, PDE6B
Cilium Assembly	5	11.1×	0.003	ARL6, CEP78, SCLT1, CEP290, ALMS1
Visual phototransduction	3	15.9×	0.024	ABCA4, RPE65, MYO7A
Centrosome maturation	3	15.5×	0.024	CEP78, CEP290, ALMS1
Anchoring of the basal body to the plasma membrane	4	9.2×	0.024	CEP78, SCLT1, CEP290, ALMS1
Sensory Perception	4	7.8×	0.041	ABCA4, RPE65, CDH23, MYO7A
MPS IIIA - Sanfilippo syndrome A	1	233.1×	0.056	SGSH
Loss of MECP2 binding ability to 5hmC-DNA	1	233.1×	0.056	MECP2
Defective visual phototransduction due to OPN1MW loss of function	1	233.1×	0.056	OPN1MW
Defective visual phototransduction due to RDH12 loss of function	1	233.1×	0.056	RDH12
Defective visual phototransduction due to OPN1LW loss of function	1	233.1×	0.056	OPN1LW
Defective visual phototransduction due to ABCA4 loss of function	1	233.1×	0.056	ABCA4
Loss of Nlp from mitotic centrosomes	3	9.7×	0.056	CEP78, CEP290, ALMS1
Loss of proteins required for interphase microtubule organization from the centrosome	3	9.7×	0.056	CEP78, CEP290, ALMS1
AURKA Activation by TPX2	3	9.3×	0.056	CEP78, CEP290, ALMS1
Recruitment of mitotic centrosome proteins and complexes	3	8.3×	0.069	CEP78, CEP290, ALMS1
Regulation of PLK1 Activity at G2/M Transition	3	7.8×	0.073	CEP78, CEP290, ALMS1
Mitotic G2-G2/M phases	3	7.8×	0.073	CEP78, CEP290, ALMS1
G2/M Transition	3	7.8×	0.073	CEP78, CEP290, ALMS1
Recruitment of NuMA to mitotic centrosomes	3	7.1×	0.089	CEP78, CEP290, ALMS1
Sensory processing of sound	2	12.6×	0.110	CDH23, MYO7A
MECP2 regulates transcription of genes involved in GABA signaling	1	77.7×	0.124	MECP2
Retinoid cycle disease events	1	58.3×	0.140	ABCA4
Diseases associated with visual transduction	1	58.3×	0.140	ABCA4
Loss of phosphorylation of MECP2 at T308	1	58.3×	0.140	MECP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 81 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	37	36.3×	1e-46	RPGR, UNC119, RPGRIP1, CACNA1F, CNGA3, CRX, DRAM2, ABCA4 (+29 more)
photoreceptor cell maintenance	12	53.1×	8e-16	CDHR1, DRAM2, ABCA4, PROM1, RHO, RP1, USH2A, CDH23 (+4 more)
retina development in camera-type eye	11	34.7×	3e-12	TTLL5, CNGA3, CRX, DRAM2, PRPH2, RP1, RP1L1, MFSD8 (+3 more)
photoreceptor cell outer segment organization	6	78.0×	9e-09	CDHR1, PRPH2, RP1, RP1L1, CRB1, PCARE
cellular response to light stimulus	6	78.0×	9e-09	RHO, RP1, CRB1, OPN1MW, TRPM1, OPN1LW
phototransduction	7	42.8×	2e-08	UNC119, GUCA1A, RHO, CABP4, OPN1MW, NR2E3, OPN1LW
detection of light stimulus involved in visual perception	6	48.0×	2e-07	CACNA1F, CACNA2D4, PRPH2, RPE65, EYS, CRB1
phototransduction, visible light	4	64.0×	2e-05	ABCA4, RHO, RP1, PDE6B
absorption of visible light	3	104.0×	1e-04	RHO, OPN1MW, OPN1LW
eye photoreceptor cell development	4	41.6×	1e-04	RPGR, CEP290, MYO7A, NR2E3
monoatomic cation transmembrane transport	4	30.8×	4e-04	CNGA3, CNGA1, CNGB3, TRPM1
sensory perception of light stimulus	3	69.3×	4e-04	USH2A, CDH23, MYO7A
cilium assembly	8	7.3×	6e-04	RPGR, CFAP410, ARL6, IFT81, FAM161A, SCLT1, CEP290, POC1B
retinoid metabolic process	4	24.5×	8e-04	ABCA4, RPE65, RDH12, RBP3
photoreceptor cell development	2	104.0×	0.005	RP1, RP1L1
protein localization to non-motile cilium	2	104.0×	0.005	RPGR, ARL6
lysosomal lumen pH elevation	2	83.2×	0.007	CLN3, OCA2
retina layer formation	3	24.0×	0.008	PROM1, ARL6, CRB1
regulation of smoothened signaling pathway	3	23.1×	0.008	ARL6, IFT81, CREBBP
photoreceptor cell morphogenesis	2	69.3×	0.009	CDHR1, CABP4
equilibrioception	2	59.4×	0.012	CDH23, MYO7A
positive regulation of excitatory postsynaptic potential	3	19.5×	0.012	NLGN3, RIMS1, CUX2
retina morphogenesis in camera-type eye	2	46.2×	0.019	PROM1, IMPG2
negative regulation of neuron apoptotic process	5	6.8×	0.019	NMNAT1, CLN3, MFSD8, MECP2, RAD21
retinal rod cell development	2	41.6×	0.022	RPGRIP1, RP1
retinal cone cell development	2	34.7×	0.031	RP1, CABP4
regulation of respiratory gaseous exchange by nervous system process	2	32.0×	0.034	NLGN3, MECP2
positive regulation of keratinocyte migration	2	32.0×	0.034	ADAM9, MAPRE2
amyloid precursor protein catabolic process	2	29.7×	0.038	ADAM9, CLN3
retina homeostasis	2	27.7×	0.042	RPE65, POC1B

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 8 · Undrugged: 67

Druggability breadth: 25 of 83 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
CACNA1F	BEPRIDIL
CACNA2D4	NIMODIPINE
CREBBP	COLCHICINE
SNRNP200	GILTERITINIB
MERTK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1F	48	4
MERTK	48	4
CREBBP	13	4
ADAM9	3	2
CACNA2D4	2	4
SNRNP200	2	4
MED12	1	2
PRPF31	1	2
RPGR	0	0
SEMA4A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1F
IMIPRAMINE	4	CACNA1F
HALOFANTRINE	4	CACNA1F
DROPERIDOL	4	CACNA1F
SAQUINAVIR	4	CACNA1F
DULOXETINE	4	CACNA1F
DIAZEPAM	4	CACNA1F
SERTINDOLE	4	CACNA1F
QUINIDINE	4	CACNA1F
LAMIVUDINE	4	CACNA1F
PIMOZIDE	4	CACNA1F
PHENYTOIN	4	CACNA1F
TERFENADINE	4	CACNA1F
CISAPRIDE	4	CACNA1F
SOLIFENACIN	4	CACNA1F
NIFEDIPINE	4	CACNA1F
DILTIAZEM	4	CACNA1F
NILOTINIB	4	CACNA1F
ASTEMIZOLE	4	CACNA1F
TERODILINE	4	CACNA1F
CLOZAPINE	4	CACNA1F
MIBEFRADIL	4	CACNA1F
DOFETILIDE	4	CACNA1F
THIORIDAZINE	4	CACNA1F
PAROXETINE	4	CACNA1F
DONEPEZIL	4	CACNA1F
IBUTILIDE	4	CACNA1F
SUNITINIB	4	CACNA1F, MERTK
HALOPERIDOL	4	CACNA1F
DASATINIB	4	CACNA1F

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
CREBBP	687	Binding:644, Functional:43
MERTK	443	Binding:442, Functional:1
CACNA1F	221	Binding:135, Functional:79, Toxicity:5, ADMET:2
SNRNP200	25	Binding:25
KCNV2	21	Binding:20, Toxicity:1
ADAM9	19	Binding:18, ADMET:1
CACNA2D4	13	Binding:13
MED12	6	Binding:6
PRPF31	6	Binding:6
OPN1LW	4	Binding:4
NMNAT1	3	Binding:3
GPR45	2	Binding:2
UNC119	1	Binding:1
CFAP410	1	Binding:1
SLC4A7	1	Binding:1
RHO	1	Binding:1
RP1	1	Binding:1
SSBP1	1	Binding:1
PANK2	1	Binding:1
MAPRE2	1	Binding:1
MECP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NMNAT1	2.7.7.1, 2.7.7.18	nicotinamide-nucleotide adenylyltransferase, nicotinate-nucleotide adenylyltransferase
ADAM9	3.4.24.B9
GUCY2D	4.6.1.2	guanylate cyclase
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase
SGSH	3.10.1.1	N-sulfoglucosamine sulfohydrolase
PANK2	2.7.1.33	pantothenate kinase
RDH12	1.1.1.105, 1.1.1.300	all-trans-retinol dehydrogenase (NAD+), NADP-retinol dehydrogenase
CREBBP	2.3.1.48	histone acetyltransferase
SNRNP200	3.6.4.13	RNA helicase
MERTK	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
CACNA1F	221
CREBBP	687
MERTK	443

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; 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)
BEPRIDIL	4	CACNA1F
IMIPRAMINE	4	CACNA1F
HALOFANTRINE	4	CACNA1F
DROPERIDOL	4	CACNA1F
SAQUINAVIR	4	CACNA1F
DULOXETINE	4	CACNA1F
DIAZEPAM	4	CACNA1F
SERTINDOLE	4	CACNA1F
QUINIDINE	4	CACNA1F
LAMIVUDINE	4	CACNA1F
PIMOZIDE	4	CACNA1F
PHENYTOIN	4	CACNA1F
TERFENADINE	4	CACNA1F
CISAPRIDE	4	CACNA1F
SOLIFENACIN	4	CACNA1F
NIFEDIPINE	4	CACNA1F
DILTIAZEM	4	CACNA1F
NILOTINIB	4	CACNA1F
ASTEMIZOLE	4	CACNA1F
TERODILINE	4	CACNA1F
CLOZAPINE	4	CACNA1F
MIBEFRADIL	4	CACNA1F
DOFETILIDE	4	CACNA1F
THIORIDAZINE	4	CACNA1F
PAROXETINE	4	CACNA1F
DONEPEZIL	4	CACNA1F
IBUTILIDE	4	CACNA1F
SUNITINIB	4	CACNA1F, MERTK
HALOPERIDOL	4	CACNA1F
DASATINIB	4	CACNA1F

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	CACNA1F, CACNA2D4, CREBBP, SNRNP200, MERTK
B	Phased (≥1) drug, not yet approved	3	ADAM9, MED12, PRPF31
C	Druggable family + PDB, no drug	10	NMNAT1, CNGA3, ABCA4, OPN1MW, OPN1LW, RHO, SGSH, PANK2, CNGA1, CNGB3
D	Druggable family + AlphaFold only, no drug	9	GUCY2D, GPR45, RPE65, USH2A, KCNV2, RDH12, CLN3, CERKL, MFSD8
E	Difficult family or no structure, no drug	48	RPGR, SEMA4A, UNC119, CFAP410, RPGRIP1, CDHR1, TTLL5, CRX, DRAM2, GUCA1A (+38 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CABP4	0	CACNA1F
EYS	0	PRPF31
RPGR	0	—
SEMA4A	0	—
UNC119	1	—
CFAP410	1	—
RPGRIP1	0	—
CDHR1	0	—
NMNAT1	3	—
TTLL5	0	—
CNGA3	0	—
CRX	0	—
DRAM2	0	—
ABCA4	0	—
GUCA1A	0	—
GUCY2D	0	—
PROM1	0	—
RAB28	0	—
PRPH2	0	—
SLC4A7	1	—
RIMS1	0	—
RAX2	0	—
PITPNM3	0	—
TLCD3B	0	—
POC1B	0	—
UBAP1L	0	—
OPN1MW	0	—
GPR45	2	—
ATF6	0	—
OPN1LW	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE1/PHASE2	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT06467344	PHASE1/PHASE2	RECRUITING	Study to Evaluate ACDN-01 in ABCA4-related Stargardt Retinopathy (STELLAR)
NCT06789445	PHASE1/PHASE2	RECRUITING	A Study to Investigate the Safety of OpCT-001 in Adults Who Have Primary Photoreceptor Disease (CLARICO)
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT05355415	Not specified	RECRUITING	Adaptive Optics Imaging of Outer Retinal Diseases
NCT06445322	Not specified	RECRUITING	Prescreening Study to Identify Potential Stargardt Participants for ACDN-01 Clinical Trials (STARPATH)
NCT07548944	Not specified	RECRUITING	Observational Study to Investigate the Short-term Effects of Transcorneal Electrical Stimulation on Visual Performance
NCT00427180	Not specified	UNKNOWN	IRIS PILOT - Extended Pilot Study With a Retinal Implant System
NCT01864486	Not specified	COMPLETED	Restoring Vision With the Intelligent Retinal Implant System (IRIS V1)in Patients With Retinal Dystrophy
NCT02670980	Not specified	COMPLETED	Compensation for Blindness With the Intelligent Retinal Implant System (IRIS V2) in Patients With Retinal Dystrophy
NCT04658251	Not specified	TERMINATED	Study of New Mutations in Cone Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHOLESTEROL	2	1
CHEMBL1867358	0	1
CHEMBL3184306	0	1