Cone dystrophy

disease

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Also known as progressive cone dystrophystationary cone dystrophy

Summary

Cone dystrophy (MONDO:0000455) is a disease (an umbrella term covering 6 Mondo subtypes) with 31 cohort genes and 4 clinical trials. The dominant Reactome pathway is Inactivation, recovery and regulation of the phototransduction cascade (3 cohort genes).

At a glance

Prevalence: Unknown (Worldwide)
Umbrella term: 6 Mondo subtypes
Cohort genes: 31
ClinVar variants: 57
Phenotypes (HPO): 5
Clinical trials: 4

Clinical features

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Very frequent (80-99%)
HP:0000551	Color vision defect	Very frequent (80-99%)
HP:0000613	Photophobia	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cone dystrophy
Mondo ID	MONDO:0000455
MeSH	D000077765
Orphanet	1871
DOID	DOID:0050795
SNOMED CT	312917007
UMLS	C0730290
MedGen	676499
GARD	0011897
NORD	991
Is cancer (heuristic)	no

Also known as: cone dystrophy · progressive cone dystrophy · stationary cone dystrophy

Data availability: 57 ClinVar variants · 7 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

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

Subtypes (6): retinal cone dystrophy type 1, cone dystrophy, X-linked, with tapetal-like sheen, cone dystrophy 3, cone dystrophy with supernormal rod response, retinal cone dystrophy 4, cone dystrophy 4

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

57 retrieved; paginated sample, class counts are floors:

20 pathogenic, 14 conflicting classifications of pathogenicity, 11 pathogenic/likely pathogenic, 7 likely pathogenic, 4 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
634547	NM_000350.3(ABCA4):c.5172G>A (p.Trp1724Ter)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7888	NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)	ABCA4	Pathogenic	reviewed by expert panel
813135	NM_000350.3(ABCA4):c.3583_3584insGT (p.Leu1195fs)	ABCA4	Pathogenic	criteria provided, single submitter
813137	NM_000350.3(ABCA4):c.4635del (p.Ser1545_Leu1546insTer)	ABCA4	Pathogenic	criteria provided, single submitter
813147	NM_000350.3(ABCA4):c.2588-7_2588-5delinsGG	ABCA4	Pathogenic	criteria provided, single submitter
865769	NM_000350.3(ABCA4):c.6005+1G>A	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
99476	NM_000350.3(ABCA4):c.6658C>T (p.Gln2220Ter)	ABCA4	Pathogenic	reviewed by expert panel
560424	NM_001042472.3(ABHD12):c.447G>A (p.Trp149Ter)	ABHD12	Pathogenic	no assertion criteria provided
438047	NM_145200.5(CABP4):c.673C>T (p.Arg225Ter)	CABP4	Pathogenic	criteria provided, multiple submitters, no conflicts
194793	NM_033100.4(CDHR1):c.2522_2528del (p.Ile841fs)	CDHR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2364	NM_201548.5(CERKL):c.769C>T (p.Arg257Ter)	CERKL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523393	NM_201548.5(CERKL):c.481+2T>G	CERKL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
428573	NM_004928.3(CFAP410):c.218G>C (p.Arg73Pro)	CFAP410	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438156	NM_001298.3(CNGA3):c.1405G>A (p.Ala469Thr)	CNGA3	Pathogenic	criteria provided, single submitter
813040	NM_001298.3(CNGA3):c.625T>C (p.Ser209Pro)	CNGA3	Pathogenic	criteria provided, single submitter
39614	NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr)	CRB1	Pathogenic	criteria provided, multiple submitters, no conflicts
623278	NM_001377295.2(GNAT2):c.620A>T (p.Glu207Val)	GNAT2	Pathogenic	criteria provided, single submitter
9355	NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys)	GUCY2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9357	NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His)	GUCY2D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265419	NM_133497.4(KCNV2):c.778A>T (p.Lys260Ter)	KCNV2	Pathogenic	criteria provided, multiple submitters, no conflicts
813184	NM_133497.4(KCNV2):c.1186G>T (p.Gly396Ter)	KCNV2	Pathogenic	criteria provided, multiple submitters, no conflicts
813186	NM_133497.4(KCNV2):c.1356+3_1356+6del	KCNV2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438390	NM_022787.4(NMNAT1):c.271G>A (p.Glu91Lys)	NMNAT1	Pathogenic/Likely pathogenic	no assertion criteria provided
813199	NM_031220.4(PITPNM3):c.1657_1660dup (p.Tyr554Ter)	PITPNM3	Pathogenic	criteria provided, single submitter
13183	NM_000322.5(PRPH2):c.424C>T (p.Arg142Trp)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813080	NM_000322.5(PRPH2):c.686_689del (p.Asn229fs)	PRPH2	Pathogenic	criteria provided, single submitter
9910	NM_001034853.2(RPGR):c.3096_3097del (p.Glu1033fs)	RPGR	Pathogenic	criteria provided, multiple submitters, no conflicts
9911	NM_001034853.2(RPGR):c.3092_3093del (p.Glu1031fs)	RPGR	Pathogenic	reviewed by expert panel
813234	NM_020366.4(RPGRIP1):c.2432T>A (p.Leu811His)	RPGRIP1	Pathogenic	criteria provided, single submitter
96125	NM_024592.5(SRD5A3):c.57G>A (p.Trp19Ter)	SRD5A3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 43 · Orphanet: 67 · 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
GUCA1A	Definitive	Autosomal dominant	cone-rod dystrophy 14	8
PDE6C	Definitive	Autosomal recessive	cone dystrophy 4	6
RP1L1	Definitive	Autosomal dominant	occult macular dystrophy	11
IRX5	Moderate	Autosomal dominant	cone dystrophy	6
IRX6	Moderate	Autosomal dominant	cone dystrophy
CNGB3	Supportive	Autosomal dominant	cone dystrophy	5
GNAT2	Supportive	Autosomal dominant	cone dystrophy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNAT2	Orphanet:1871	Progressive cone dystrophy
GNAT2	Orphanet:49382	Achromatopsia
PDE6C	Orphanet:1871	Progressive cone dystrophy
PDE6C	Orphanet:49382	Achromatopsia
IRX5	Orphanet:314555	Facial dysmorphism-ocular anomalies-osteopenia-intellectual disability-dental anomalies syndrome
RP1L1	Orphanet:247834	Occult macular dystrophy
RP1L1	Orphanet:791	Retinitis pigmentosa
CNGB3	Orphanet:1871	Progressive cone dystrophy
CNGB3	Orphanet:49382	Achromatopsia
CNGB3	Orphanet:827	Stargardt disease
GUCA1A	Orphanet:1871	Progressive cone dystrophy
GUCA1A	Orphanet:1872	Cone rod dystrophy
GUCA1A	Orphanet:75377	Central areolar choroidal dystrophy
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
SAG	Orphanet:75382	Oguchi disease
SAG	Orphanet:791	Retinitis pigmentosa
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
CABP4	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
CABP4	Orphanet:98784	Sleep-related hypermotor epilepsy
CDHR1	Orphanet:1872	Cone rod dystrophy
CDHR1	Orphanet:791	Retinitis pigmentosa
ABHD12	Orphanet:171848	Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome
NMNAT1	Orphanet:1872	Cone rod dystrophy
NMNAT1	Orphanet:65	Leber congenital amaurosis
WDR19	Orphanet:1515	Cranioectodermal dysplasia
WDR19	Orphanet:3156	Senior-Loken syndrome
WDR19	Orphanet:474	Jeune syndrome
WDR19	Orphanet:93592	Juvenile nephronophthisis
KCNV2	Orphanet:209932	Cone dystrophy with supernormal rod response
CACNA2D4	Orphanet:1872	Cone rod dystrophy
CACNA2D4	Orphanet:714070	Incomplete congenital stationary night blindness, Schubert-Bornschein type
PITPNM3	Orphanet:1872	Cone rod dystrophy
CNGA3	Orphanet:1872	Cone rod dystrophy
CNGA3	Orphanet:49382	Achromatopsia
CERKL	Orphanet:791	Retinitis pigmentosa
CRB1	Orphanet:251295	Pigmented paravenous retinochoroidal atrophy
CRB1	Orphanet:35612	Nanophthalmos
CRB1	Orphanet:65	Leber congenital amaurosis
CRB1	Orphanet:791	Retinitis pigmentosa
SRD5A3	Orphanet:324737	SRD5A3-CDG
ABCA4	Orphanet:1872	Cone rod dystrophy

Cohort genes → proteins

31 cohort genes, 31 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	31

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNAT2	HGNC:4394	ENSG00000134183	P19087	Guanine nucleotide-binding protein G(t) subunit alpha-2	gencc,clinvar
PDE6C	HGNC:8787	ENSG00000095464	P51160	Cone cGMP-specific 3’,5’-cyclic phosphodiesterase subunit alpha'	gencc,clinvar
IRX5	HGNC:14361	ENSG00000176842	P78411	Iroquois-class homeodomain protein IRX-5	gencc
IRX6	HGNC:14675	ENSG00000159387	P78412	Iroquois-class homeodomain protein IRX-6	gencc
RP1L1	HGNC:15946	ENSG00000183638	Q8IWN7	Retinitis pigmentosa 1-like 1 protein	gencc
CNGB3	HGNC:2153	ENSG00000170289	Q9NQW8	Cyclic nucleotide-gated channel beta-3	gencc
GUCA1A	HGNC:4678	ENSG00000048545	P43080	Guanylyl cyclase-activating protein 1	gencc
RNF7	HGNC:10070	ENSG00000114125	Q9UBF6	RING-box protein 2	clinvar
RPGR	HGNC:10295	ENSG00000156313	Q92834	X-linked retinitis pigmentosa GTPase regulator	clinvar
SAG	HGNC:10521	ENSG00000130561	P10523	S-arrestin	clinvar
CFAP410	HGNC:1260	ENSG00000160226	O43822	Cilia- and flagella-associated protein 410	clinvar
RPGRIP1	HGNC:13436	ENSG00000092200	Q96KN7	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	clinvar
CABP4	HGNC:1386	ENSG00000175544	P57796	Calcium-binding protein 4	clinvar
CDHR1	HGNC:14550	ENSG00000148600	Q96JP9	Cadherin-related family member 1	clinvar
ABHD12	HGNC:15868	ENSG00000100997	Q8N2K0	Lysophosphatidylserine lipase ABHD12	clinvar
NMNAT1	HGNC:17877	ENSG00000173614	Q9HAN9	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	clinvar
WDR19	HGNC:18340	ENSG00000157796	Q8NEZ3	WD repeat-containing protein 19	clinvar
KCNV2	HGNC:19698	ENSG00000168263	Q8TDN2	Potassium voltage-gated channel subfamily V member 2	clinvar
CACNA2D4	HGNC:20202	ENSG00000151062	Q7Z3S7	Voltage-dependent calcium channel subunit alpha-2/delta-4	clinvar
PITPNM3	HGNC:21043	ENSG00000091622	Q9BZ71	Membrane-associated phosphatidylinositol transfer protein 3	clinvar
CNGA3	HGNC:2150	ENSG00000144191	Q16281	Cyclic nucleotide-gated channel alpha-3	clinvar
CERKL	HGNC:21699	ENSG00000188452	Q49MI3	Ceramide kinase-like protein	clinvar
CRB1	HGNC:2343	ENSG00000134376	P82279	Protein crumbs homolog 1	clinvar
SRD5A3	HGNC:25812	ENSG00000128039	Q9H8P0	Polyprenal reductase	clinvar
RGL4	HGNC:31911	ENSG00000159496	Q8IZJ4	Ral-GDS-related protein	clinvar
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	clinvar
GUCY2D	HGNC:4689	ENSG00000132518	Q02846	Retinal guanylyl cyclase 1	clinvar
BBS5	HGNC:970	ENSG00000163093	Q8N3I7	BBSome complex member BBS5	clinvar
RAB28	HGNC:9768	ENSG00000157869	P51157	Ras-related protein Rab-28	clinvar
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	clinvar
RGR	HGNC:9990	ENSG00000148604	P47804	RPE-retinal G protein-coupled receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNAT2	Guanine nucleotide-binding protein G(t) subunit alpha-2	Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.
PDE6C	Cone cGMP-specific 3’,5’-cyclic phosphodiesterase subunit alpha'	As cone-specific cGMP phosphodiesterase, it plays an essential role in light detection and cone phototransduction by rapidly decreasing intracellular levels of cGMP.
IRX5	Iroquois-class homeodomain protein IRX-5	Establishes the cardiac repolarization gradient by its repressive actions on the KCND2 potassium-channel gene.
IRX6	Iroquois-class homeodomain protein IRX-6	Transcription factor.
RP1L1	Retinitis pigmentosa 1-like 1 protein	Required for the differentiation of photoreceptor cells.
CNGB3	Cyclic nucleotide-gated channel beta-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
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.
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.
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.
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.
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.
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.
CDHR1	Cadherin-related family member 1	Potential calcium-dependent cell-adhesion protein.
ABHD12	Lysophosphatidylserine lipase ABHD12	Lysophosphatidylserine (LPS) lipase that mediates the hydrolysis of lysophosphatidylserine, a class of signaling lipids that regulates immunological and neurological processes.
NMNAT1	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP.
WDR19	WD repeat-containing protein 19	As component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in cilia function and/or assembly.
KCNV2	Potassium voltage-gated channel subfamily V member 2	Potassium channel subunit.
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.
PITPNM3	Membrane-associated phosphatidylinositol transfer protein 3	Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro).
CNGA3	Cyclic nucleotide-gated channel alpha-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
CERKL	Ceramide kinase-like protein	Has no detectable ceramide-kinase activity.
CRB1	Protein crumbs homolog 1	Plays a role in photoreceptor morphogenesis in the retina.
SRD5A3	Polyprenal reductase	Plays a key role in early steps of protein N-linked glycosylation by being involved in the conversion of polyprenol into dolichol.
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…
GUCY2D	Retinal guanylyl cyclase 1	Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.
BBS5	BBSome complex member BBS5	The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.
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.
RGR	RPE-retinal G protein-coupled receptor	Receptor for all-trans- and 11-cis-retinal.

Protein-family classification

Druggable: 9 · Difficult: 5 · Unknown: 17 · 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
Ion channel	3	10.8×	0.019
Transporter	1	2.5×	0.579
Kinase	2	1.8×	0.579
Transcription factor	5	1.3×	0.579
Other/Unknown	17	1.0×	0.743
Enzyme (other)	2	0.8×	0.743
GPCR	1	0.8×	0.743

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNAT2	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
PDE6C	Transcription factor	no		PDEase_catalytic_dom, GAF, HD/PDEase_dom
IRX5	Transcription factor	no		HD, Iroquois_homeo, KN_HD
IRX6	Transcription factor	no		HD, Iroquois_homeo, KN_HD
RP1L1	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
CNGB3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
GUCA1A	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
RNF7	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_H2
RPGR	Other/Unknown	no		Reg_chr_condens, RCC1/BLIP-II, Signaling_Regulatory_Domain
SAG	Other/Unknown	no		Arrestin, Arrestin-like_N, Arrestin-like_C
CFAP410	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
RPGRIP1	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
CABP4	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CDHR1	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
ABHD12	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
NMNAT1	Enzyme (other)	yes	2.7.7.1	Cyt_trans-like, NadD/NMNAT, Rossmann-like_a/b/a_fold
WDR19	Transcription factor	no		WD40_rpt, TPR-like_helical_dom_sf, WD40/YVTN_repeat-like_dom_sf
KCNV2	Ion channel	yes		T1-type_BTB, K_chnl_volt-dep_Kv, K_chnl_volt-dep_Kv5/Kv9
CACNA2D4	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
PITPNM3	Other/Unknown	no		PI_transfer, DDHD_dom, HAD_sf
CNGA3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
CERKL	Kinase	yes		Diacylglycerol_kinase_cat_dom, NAD/diacylglycerol_kinase_sf, ATP-NAD_kinase_N
CRB1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
SRD5A3	Enzyme (other)	yes	1.3.1.22	3-oxo-5_a-steroid_4-DH_C, Dfg10/SRD5A3
RGL4	Other/Unknown	no		RASGEF_cat_dom, Ras-like_GEF, Ras_GEF_dom_sf
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR
GUCY2D	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom
BBS5	Other/Unknown	no		BBL5, PH-like_dom_sf, BBS5_PH
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
RGR	GPCR	yes		GPCR_Rhodpsn, RPE_GPCR, GPCR_Rhodpsn_7TM

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	31
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
primordial germ cell in gonad	4
right uterine tube	4
bronchial epithelial cell	3
skin of abdomen	3
hindlimb stylopod muscle	3
pigmented layer of retina	3
sperm	3
endothelial cell	3
olfactory segment of nasal mucosa	3
secondary oocyte	2
bone marrow cell	2
buccal mucosa cell	2
nucleus accumbens	2
left testis	2
adenohypophysis	2
ganglionic eminence	2
ventricular zone	2
oocyte	1
cerebellar hemisphere	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNAT2	153	tissue_specific	marker	oocyte, primordial germ cell in gonad, secondary oocyte
PDE6C	159	tissue_specific	marker	secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere
IRX5	163	broad	marker	upper leg skin, bronchial epithelial cell, skin of abdomen
IRX6	95	tissue_specific	marker	apex of heart, skin of abdomen, hindlimb stylopod muscle
RP1L1	30	tissue_specific	yes	primordial germ cell in gonad, buccal mucosa cell, bone marrow cell
CNGB3	161	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, diaphragm
GUCA1A	52	broad	marker	nucleus accumbens, putamen, hypothalamus
RNF7	292	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland
RPGR	281	ubiquitous	marker	sperm, bronchial epithelial cell, right uterine tube
SAG	106	tissue_specific	marker	nucleus accumbens, male germ line stem cell (sensu Vertebrata) in testis, left testis
CFAP410	190	ubiquitous	marker	right uterine tube, adenohypophysis, right frontal lobe
RPGRIP1	168	tissue_specific	marker	left testis, sperm, right testis
CABP4	226	broad	marker	vena cava, cardia of stomach, ventral tegmental area
CDHR1	186	broad	marker	upper arm skin, skin of leg, skin of abdomen
ABHD12	256	ubiquitous	marker	C1 segment of cervical spinal cord, prefrontal cortex, spinal cord
NMNAT1	225	ubiquitous	yes	hindlimb stylopod muscle, muscle of leg, mucosa of transverse colon
WDR19	269	ubiquitous	marker	right uterine tube, bronchial epithelial cell, adenohypophysis
KCNV2	61	tissue_specific	marker	sperm, male germ cell, primordial germ cell in gonad
CACNA2D4	136	broad	yes	monocyte, leukocyte, granulocyte
PITPNM3	222	broad	marker	pancreatic ductal cell, endothelial cell, Brodmann (1909) area 23
CNGA3	110	tissue_specific	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence
CERKL	122	tissue_specific	marker	islet of Langerhans, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis
CRB1	163	broad	marker	ganglionic eminence, ventricular zone, endothelial cell
SRD5A3	254	ubiquitous	marker	palpebral conjunctiva, gall bladder, olfactory segment of nasal mucosa
RGL4	155	broad	marker	bone marrow, bone marrow cell, blood
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
GUCY2D	121	tissue_specific	marker	buccal mucosa cell, esophagus mucosa, lower esophagus mucosa
BBS5	140	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, olfactory segment of nasal mucosa
RAB28	284	ubiquitous	marker	tibia, germinal epithelium of ovary, endothelial cell
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 54.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNF7	2,453
NMNAT1	2,424
RPGR	2,231
SAG	1,927
KCNV2	1,908
CABP4	1,897
GNAT2	1,675
RAB28	1,563
IRX6	1,533
ABCA4	1,532

Intra-cohort edges

A	B	Sources
ABCA4	CDHR1	string_interaction
ABCA4	CERKL	string_interaction
ABCA4	CNGB3	string_interaction
ABCA4	GUCY2D	string_interaction
ABCA4	KCNV2	string_interaction
ABCA4	PITPNM3	string_interaction
ABCA4	PRPH2	string_interaction
ABCA4	RGR	string_interaction
ABCA4	RP1L1	string_interaction
ABCA4	RPGR	string_interaction
CABP4	CACNA2D4	string_interaction
CACNA2D4	KCNV2	string_interaction
CDHR1	CERKL	string_interaction
CDHR1	GUCY2D	string_interaction
CDHR1	KCNV2	string_interaction
CDHR1	PITPNM3	string_interaction
CDHR1	PRPH2	string_interaction
CDHR1	RAB28	string_interaction
CDHR1	RPGRIP1	string_interaction
CERKL	RGR	string_interaction
CERKL	RP1L1	string_interaction
CERKL	RPGR	string_interaction
CNGA3	CNGB3	biogrid_interaction, string_interaction
CNGA3	GNAT2	string_interaction
CNGA3	GUCY2D	string_interaction
CNGA3	KCNV2	string_interaction
CNGA3	PDE6C	string_interaction
CNGA3	RPGR	string_interaction
CNGB3	GNAT2	string_interaction
CNGB3	GUCY2D	string_interaction
CNGB3	KCNV2	string_interaction
CNGB3	PDE6C	string_interaction
CNGB3	RPGR	string_interaction
CNGB3	RPGRIP1	string_interaction
GNAT2	PDE6C	string_interaction
GUCA1A	GUCY2D	string_interaction
GUCA1A	RPGRIP1	string_interaction
GUCY2D	KCNV2	string_interaction
GUCY2D	NMNAT1	string_interaction
GUCY2D	PDE6C	string_interaction
GUCY2D	PITPNM3	string_interaction
GUCY2D	PRPH2	string_interaction
GUCY2D	RPGRIP1	string_interaction
IRX5	IRX6	string_interaction
KCNV2	PDE6C	string_interaction
KCNV2	RPGRIP1	string_interaction
PITPNM3	RAB28	string_interaction
PITPNM3	RPGRIP1	string_interaction
PRPH2	RP1L1	string_interaction
PRPH2	RPGR	string_interaction

Structural data

PDB: 16 · AlphaFold-only: 15 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CNGA3	Q16281	10
CNGB3	Q9NQW8	9
ABCA4	P78363	8
PDE6C	P51160	7
RNF7	Q9UBF6	7
NMNAT1	Q9HAN9	6
WDR19	Q8NEZ3	4
RPGR	Q92834	3
GNAT2	P19087	2
RAB28	P51157	2
CFAP410	O43822	1
RPGRIP1	Q96KN7	1
PITPNM3	Q9BZ71	1
CRB1	P82279	1
BBS5	Q8N3I7	1
PRPH2	P23942	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RGR	P47804	90.04
SRD5A3	Q9H8P0	89.07
ABHD12	Q8N2K0	85.60
SAG	P10523	85.44
GUCY2D	Q02846	82.37
CACNA2D4	Q7Z3S7	81.69
CERKL	Q49MI3	79.82
CDHR1	Q96JP9	78.79
KCNV2	Q8TDN2	75.55
GUCA1A	P43080	71.28
CABP4	P57796	65.01
RGL4	Q8IZJ4	62.88
IRX6	P78412	55.29
IRX5	P78411	55.14
RP1L1	Q8IWN7	38.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 53. Enrichment computed across 31 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inactivation, recovery and regulation of the phototransduction cascade	3	68.0×	5e-04	SAG, GUCA1A, GUCY2D
Defective SRD5A3 causes SRD5A3-CDG, KHRZ	1	815.7×	0.017	SRD5A3
Defective visual phototransduction due to ABCA4 loss of function	1	815.7×	0.017	ABCA4
Visual phototransduction	2	37.1×	0.017	SAG, ABCA4
Diseases associated with glycosylation precursor biosynthesis	1	407.9×	0.026	SRD5A3
Retinoid cycle disease events	1	203.9×	0.032	ABCA4
Diseases associated with visual transduction	1	203.9×	0.032	ABCA4
Diseases of the neuronal system	1	203.9×	0.032	ABCA4
Synthesis of PI	1	163.1×	0.032	PITPNM3
Arachidonate production from DAG	1	163.1×	0.032	ABHD12
Synthesis of dolichyl-phosphate	1	116.5×	0.041	SRD5A3
Sensory Perception	2	13.6×	0.041	SAG, ABCA4
The phototransduction cascade	1	90.6×	0.042	SAG
Opsins	1	90.6×	0.042	RGR
Androgen biosynthesis	1	74.2×	0.047	SRD5A3
Activation of the phototransduction cascade	1	68.0×	0.048	SAG
Metabolism of steroid hormones	1	37.1×	0.078	SRD5A3
The canonical retinoid cycle in rods (twilight vision)	1	37.1×	0.078	ABCA4
BBSome-mediated cargo-targeting to cilium	1	35.5×	0.078	BBS5
Effects of PIP2 hydrolysis	1	32.6×	0.079	ABHD12
Inactivation of CSF3 (G-CSF) signaling	1	31.4×	0.079	RNF7
Nicotinate metabolism	1	28.1×	0.084	NMNAT1
Synthesis of substrates in N-glycan biosythesis	1	20.9×	0.108	SRD5A3
G alpha (i) signalling events	2	5.6×	0.108	GNAT2, RGR
Cargo trafficking to the periciliary membrane	1	17.7×	0.114	BBS5
Voltage gated Potassium channels	1	17.4×	0.114	KCNV2
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	14.8×	0.128	SRD5A3
Intraflagellar transport	1	14.3×	0.128	WDR19
Ca2+ pathway	1	12.8×	0.134	GNAT2
Hedgehog ‘off’ state	1	12.8×	0.134	WDR19

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 31 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	15	38.5×	8e-19	GNAT2, PDE6C, RPGR, RPGRIP1, CABP4, IRX5, RP1L1, CNGA3 (+7 more)
photoreceptor cell outer segment organization	4	135.9×	1e-06	CDHR1, RP1L1, CRB1, PRPH2
detection of light stimulus involved in visual perception	4	83.6×	7e-06	GNAT2, CACNA2D4, CRB1, PRPH2
phototransduction	4	64.0×	2e-05	GNAT2, CABP4, GUCA1A, RGR
retinal cone cell development	3	135.9×	4e-05	GNAT2, PDE6C, CABP4
photoreceptor cell maintenance	4	46.3×	4e-05	CDHR1, RP1L1, CRB1, ABCA4
photoreceptor cell morphogenesis	2	181.2×	1e-03	CABP4, CDHR1
retinal bipolar neuron differentiation	2	181.2×	1e-03	CABP4, IRX5
phototransduction, visible light	2	83.6×	0.004	PDE6C, ABCA4
retina development in camera-type eye	3	24.7×	0.004	RP1L1, CNGA3, PRPH2
gonad development	2	72.5×	0.005	IRX5, WDR19
cellular response to light stimulus	2	68.0×	0.005	CRB1, RGR
cell development	2	57.2×	0.007	IRX5, IRX6
monoatomic cation transport	2	49.4×	0.008	CNGA3, CNGB3
cilium assembly	4	9.5×	0.008	RPGR, CFAP410, WDR19, BBS5
monoatomic cation transmembrane transport	2	40.3×	0.011	CNGA3, CNGB3
embryonic cranial skeleton morphogenesis	2	37.5×	0.012	IRX5, WDR19
response to low light intensity stimulus	1	543.6×	0.014	PRPH2
polyprenol catabolic process	1	543.6×	0.014	SRD5A3
positive regulation of guanylate cyclase activity	1	543.6×	0.014	GUCA1A
camera-type eye photoreceptor cell development	1	543.6×	0.014	CRB1
post-embryonic retina morphogenesis in camera-type eye	1	271.8×	0.024	CRB1
inorganic cation import across plasma membrane	1	271.8×	0.024	CNGA3
background adaptation	1	271.8×	0.024	GNAT2
phospholipid transfer to membrane	1	181.2×	0.031	ABCA4
homeostasis of number of retina cells	1	181.2×	0.031	GNAT2
establishment of bipolar cell polarity involved in cell morphogenesis	1	181.2×	0.031	CRB1
phosphatidylserine catabolic process	1	135.9×	0.031	ABHD12
photoreceptor cell development	1	135.9×	0.031	RP1L1
ear morphogenesis	1	135.9×	0.031	WDR19

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 28

Druggability breadth: 7 of 31 evidence-associated genes (23%) 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
PDE6C	VARDENAFIL
ABHD12	ORLISTAT
CACNA2D4	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE6C	6	4
ABHD12	2	4
CACNA2D4	2	4
GNAT2	0	0
IRX5	0	0
IRX6	0	0
RP1L1	0	0
CNGB3	0	0
GUCA1A	0	0
RNF7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE6C
SILDENAFIL	4	PDE6C
TADALAFIL	4	PDE6C
DIPYRIDAMOLE	4	PDE6C
ORLISTAT	4	ABHD12
DRONABINOL	4	ABHD12
NIMODIPINE	4	CACNA2D4
TACRINE	4	CACNA2D4
ZAPRINAST	2	PDE6C
TBA-7371	2	PDE6C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PDE6C	103	Binding:97, ADMET:6
ABHD12	35	Binding:31, Toxicity:3, ADMET:1
KCNV2	21	Binding:20, Toxicity:1
CACNA2D4	13	Binding:13
NMNAT1	3	Binding:3
CFAP410	1	Binding:1
SRD5A3	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
SRD5A3	1.3.1.22, 1.3.1.94, 1.3.1.B13	3-oxo-5alpha-steroid 4-dehydrogenase (NADP+), polyprenal reductase,
GUCY2D	4.6.1.2	guanylate cyclase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PDE6C	103

Pharmacogenomics

Cohort genes with a PharmGKB record: 31; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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)
VARDENAFIL	4	PDE6C
SILDENAFIL	4	PDE6C
TADALAFIL	4	PDE6C
DIPYRIDAMOLE	4	PDE6C
ORLISTAT	4	ABHD12
DRONABINOL	4	ABHD12
NIMODIPINE	4	CACNA2D4
TACRINE	4	CACNA2D4
ZAPRINAST	2	PDE6C
TBA-7371	2	PDE6C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	PDE6C, ABHD12, CACNA2D4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	4	CNGB3, NMNAT1, CNGA3, ABCA4
D	Druggable family + AlphaFold only, no drug	5	KCNV2, CERKL, SRD5A3, GUCY2D, RGR
E	Difficult family or no structure, no drug	19	GNAT2, IRX5, IRX6, RP1L1, GUCA1A, RNF7, RPGR, SAG, CFAP410, RPGRIP1 (+9 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GNAT2	0	PDE6C
CNGB3	0	PDE6C
CNGA3	0	PDE6C
IRX5	0	—
IRX6	0	—
RP1L1	0	—
GUCA1A	0	—
RNF7	0	—
RPGR	0	—
SAG	0	—
CFAP410	1	—
RPGRIP1	0	—
CABP4	0	—
CDHR1	0	—
NMNAT1	3	—
WDR19	0	—
KCNV2	21	—
PITPNM3	0	—
CERKL	0	—
CRB1	0	—
SRD5A3	1	—
RGL4	0	—
ABCA4	0	—
GUCY2D	0	—
BBS5	0	—
RAB28	0	—
PRPH2	0	—
RGR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT05355415	Not specified	RECRUITING	Adaptive Optics Imaging of Outer Retinal Diseases
NCT03990727	Not specified	UNKNOWN	Phenotype Correlates Genotype of Inherited Retina Dystrophies, Retinitis Pigmentosa, Con>Rod Dystrophies.
NCT04658251	Not specified	TERMINATED	Study of New Mutations in Cone Disorders

Cohort genes: GNAT2, PDE6C, IRX5, IRX6, RP1L1, CNGB3, GUCA1A, RNF7, RPGR, SAG, CFAP410, RPGRIP1, CABP4, CDHR1, ABHD12, NMNAT1, WDR19, KCNV2, CACNA2D4, PITPNM3, CNGA3, CERKL, CRB1, SRD5A3, RGL4, ABCA4, GUCY2D, BBS5, RAB28, PRPH2, RGR