Open-angle glaucoma

Summary

Open-angle glaucoma (MONDO:0005338) is a disease (an umbrella term covering 7 Mondo subtypes) with 75 cohort genes (1,387 GWAS associations across 60 studies) and 618 clinical trials. The dominant Reactome pathway is Kidney development (3 cohort genes). Top therapeutic interventions include timolol, latanoprost, and travoprost.

At a glance

• Umbrella term: 7 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 1,387
• ClinVar variants: 271
• Clinical trials: 618

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	open-angle glaucoma
Mondo ID	MONDO:0005338
EFO	EFO:0004190
MeSH	D005902
DOID	DOID:1067
ICD-10-CM	H40.1
NCIT	C34641
SNOMED CT	46168003, 84494001
UMLS	C0017612
MedGen	6611
Is cancer (heuristic)	no

Also known as: glaucoma, primary open angle · open angle glaucoma · pigmentary glaucoma · POAG · primary open angle glaucoma

Data availability: 271 ClinVar variants · 255 ClinGen variant curations · 1,387 GWAS associations (60 studies) · 2 GenCC gene-disease records · 163 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › glaucoma › open-angle glaucoma

Related subtypes (10): glaucomatous atrophy of optic disk, hypersecretion glaucoma, aqueous misdirection, phacogenic glaucoma, traumatic glaucoma, angle-closure glaucoma, borderline glaucoma, steroid-induced glaucoma, hereditary glaucoma, secondary early-onset glaucoma

Subtypes (7): residual stage of open angle glaucoma, low tension glaucoma, glaucoma 1, open angle, P, glaucoma type 1C, glaucoma 1, open angle, O, juvenile open angle glaucoma, OPTN-related open angle glaucoma

Genetics & variants

GWAS landscape

1,387 GWAS associations across 60 studies. Top hits map to 23 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs944801	2e-171	CDKN2B-AS1	C	0.23
rs6475604	2e-148	CDKN2B-AS1	T	0.23
rs7528177	6e-143	TMCO1	A	0.32
rs4657477	8e-141	TMCO1	T	0.32
rs2790053	2e-122	TMCO1	C	0.24
rs2472494	1e-119	ABCA1 - CT70	T	0.18
rs33912345	6e-85	C14orf39, SIX6	A	0.16
rs9913911	6e-83	GAS7	A	0.16
rs9330348	3e-78	AFAP1	C	0.16
rs2790049	6e-75	TMCO1-AS1, TMCO1	?	0.26
rs34935520	2e-70	C14orf39 - SALRNA1	A	0.15
rs10257125	8e-66	CAV2 - CAV1	A	0.16
rs10233003	1e-64	CAV2	A	0.16
rs1336980	4e-64	LMX1B	C	0.14
rs2814471	2e-62	TMCO1, TMCO1-AS1	C	1.37
rs2275241	4e-57	LMX1B-DT	A	0.14
rs9853115	8e-56	DGKG - LINC02020	A	0.14
rs2745572	9e-52	ELF2P2 - FOXCUT	A	0.14
rs938604	1e-49	AFAP1	A	0.11
rs373639805	6e-49	LOXL1	G	0.21
rs7686202	9e-48	AFAP1	?	0.14
rs2326788	1e-47	CASC20	A	0.12
rs6140009	6e-43	CASC20	T	0.12
rs2472493	6e-43	ABCA1 - CT70	A	0.14
rs74315329	1e-42	MYOCOS, MYOC	A	1.1
rs1397894	4e-41	RPL6P25 - SLC6A15	A	0.12
rs7524755	8e-41	TMCO1	T	1.37
rs6434068	3e-40	FMNL2	C	0.11
rs446011	6e-40	RPL6P25 - SLC6A15	A	0.11
rs6845653	7e-40	AFAP1	T	0.84

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475871	Verma A	2024	30,309	84,722	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90310210	Han X	2023	29,241	350,181	Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci.
GCST90310211	Han X	2023	29,241	350,181	Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci.
GCST90011770	Gharahkhani P	2021	23,963	306,942	Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.
GCST90011766	Gharahkhani P	2021	16,677	199,580	Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.
GCST90399725	Zhou W	2022	16,355	1,156,550	Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease.
GCST90011767	Gharahkhani P	2021	15,229	177,473	Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.
GCST006065	Choquet H	2018	10,523	203,579	A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.
GCST90399724	Zhou W	2022	9,715	260,245	Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease.
GCST011438	Gharahkhani P	2021	9,179	134,471	Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	1
Tier 3: regulatory	4
Tier 4: intronic/intergenic	42

MAF distribution

Bucket	Variants
common (>=0.05)	49
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	35
intergenic_variant	6
regulatory_region_variant	4
missense_variant	2
non_coding_transcript_exon_variant	1
splice_region_variant	1
stop_gained	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs944801	9	22051671	G>A,C	0.05	intron_variant	CDKN2B-AS1	2e-171	Tier 4: intronic/intergenic
rs6475604	9	22052735	T>A,C,G	0.05	intron_variant	CDKN2B-AS1	2e-148	Tier 4: intronic/intergenic
rs7528177	1	165763863	A>C,G,T	0.05	intron_variant	TMCO1	6e-143	Tier 4: intronic/intergenic
rs4657477	1	165766938	C>G,T	0.05	intron_variant	TMCO1	8e-141	Tier 4: intronic/intergenic
rs2790053	1	165768467	C>A,G,T	0.05	intron_variant	TMCO1	2e-122	Tier 4: intronic/intergenic
rs2472494	9	104933258	T>A,C	0.05	intron_variant	ABCA1 - CT70	1e-119	Tier 4: intronic/intergenic
rs33912345	14	60509819	C>A,G	0.05	missense_variant	C14orf39, SIX6	6e-85	Tier 1: coding
rs9913911	17	10127866	A>G	0.05	intron_variant	GAS7	6e-83	Tier 4: intronic/intergenic
rs9330348	4	7882160	C>G	0.05	intron_variant	AFAP1	3e-78	Tier 4: intronic/intergenic
rs2790049	1	165774286	A>C,G,T	0.05	non_coding_transcript_exon_variant	TMCO1-AS1, TMCO1	6e-75	Tier 4: intronic/intergenic
rs34935520	14	60624683	G>A	0.05	intron_variant	C14orf39 - SALRNA1	2e-70	Tier 4: intronic/intergenic
rs10257125	7	116522252	A>T	0.05	regulatory_region_variant	CAV2 - CAV1	8e-66	Tier 3: regulatory
rs10233003	7	116503608	C>A	0.05	intron_variant	CAV2	1e-64	Tier 4: intronic/intergenic
rs1336980	9	126615576	G>A,C,T	0.05	splice_region_variant	LMX1B	4e-64	Tier 2: splice/UTR
rs2814471	1	165770361	C>A,G,T	0.05	intron_variant	TMCO1, TMCO1-AS1	2e-62	Tier 4: intronic/intergenic
rs2275241	9	126608297	G>A	0.05	intron_variant	LMX1B-DT	4e-57	Tier 4: intronic/intergenic
rs9853115	3	186413811	T>A,G	0.05	regulatory_region_variant	DGKG - LINC02020	8e-56	Tier 3: regulatory
rs2745572	6	1548134	A>C,G,T	0.05	intron_variant	ELF2P2 - FOXCUT	9e-52	Tier 4: intronic/intergenic
rs938604	4	7902636	G>A	0.05	intron_variant	AFAP1	1e-49	Tier 4: intronic/intergenic
rs373639805	15	73931070		0.155	intron_variant	LOXL1	6e-49	Tier 4: intronic/intergenic
rs7686202	4	7896850	C>T	0.05	intron_variant	AFAP1	9e-48	Tier 4: intronic/intergenic
rs2326788	20	6489447	G>A	0.05	intron_variant	CASC20	1e-47	Tier 4: intronic/intergenic
rs6140009	20	6492407	C>G,T	0.05	intron_variant	CASC20	6e-43	Tier 4: intronic/intergenic
rs2472493	9	104933567	G>A,C,T	0.451	intron_variant	ABCA1 - CT70	6e-43	Tier 4: intronic/intergenic
rs74315329	1	171636338	G>A,C		stop_gained	MYOCOS, MYOC	1e-42	Tier 1: coding
rs1397894	12	83630340	G>A	0.05	intergenic_variant	RPL6P25 - SLC6A15	4e-41	Tier 4: intronic/intergenic
rs7524755	1	165725660	T>A,C,G	0.05	intergenic_variant	TMCO1	8e-41	Tier 4: intronic/intergenic
rs6434068	2	152501027	G>C	0.05	intron_variant	FMNL2	3e-40	Tier 4: intronic/intergenic
rs446011	12	83579508	A>C,G,T	0.05	intergenic_variant	RPL6P25 - SLC6A15	6e-40	Tier 4: intronic/intergenic
rs6845653	4	7897652	C>A,T	0.05	intron_variant	AFAP1	7e-40	Tier 4: intronic/intergenic

ClinVar germline variants

271 retrieved; paginated sample, class counts are floors:

166 uncertain significance, 45 likely benign, 35 likely pathogenic, 14 pathogenic, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1342196	NM_000261.2(MYOC):c.752T>C (p.Val251Ala)	MYOC	Pathogenic	reviewed by expert panel
1342202	NM_000261.2(MYOC):c.1130C>T (p.Thr377Met)	MYOC	Pathogenic	reviewed by expert panel
1342203	NM_000261.2(MYOC):c.1139A>C (p.Asp380Ala)	MYOC	Pathogenic	reviewed by expert panel
1439558	NM_000261.2(MYOC):c.1021T>C (p.Ser341Pro)	MYOC	Pathogenic	reviewed by expert panel
1686785	NM_000261.2(MYOC):c.1440C>G (p.Asn480Lys)	MYOC	Pathogenic	reviewed by expert panel
7946	NM_000261.2(MYOC):c.1309T>C (p.Tyr437His)	MYOC	Pathogenic	reviewed by expert panel
7947	NM_000261.2(MYOC):c.1091G>T (p.Gly364Val)	MYOC	Pathogenic	reviewed by expert panel
7948	NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu)	MYOC	Pathogenic	reviewed by expert panel
7949	NM_000261.2(MYOC):c.1102C>T (p.Gln368Ter)	MYOC	Pathogenic	reviewed by expert panel
7951	NM_000261.2(MYOC):c.1440C>A (p.Asn480Lys)	MYOC	Pathogenic	reviewed by expert panel
7952	NM_000261.2(MYOC):c.1099G>A (p.Gly367Arg)	MYOC	Pathogenic	reviewed by expert panel
7954	NM_000261.2(MYOC):c.1267A>G (p.Lys423Glu)	MYOC	Pathogenic	reviewed by expert panel
7956	NM_000261.2(MYOC):c.1297T>C (p.Cys433Arg)	MYOC	Pathogenic	reviewed by expert panel
7960	NM_000261.2(MYOC):c.754G>A (p.Gly252Arg)	MYOC	Pathogenic	reviewed by expert panel
1173106	NM_000261.2(MYOC):c.1435T>C (p.Tyr479His)	MYOC	Likely pathogenic	reviewed by expert panel
1342197	NM_000261.2(MYOC):c.856T>C (p.Trp286Arg)	MYOC	Likely pathogenic	reviewed by expert panel
1342198	NM_000261.2(MYOC):c.976G>C (p.Gly326Arg)	MYOC	Likely pathogenic	reviewed by expert panel
1342205	NM_000261.2(MYOC):c.1150G>A (p.Asp384Asn)	MYOC	Likely pathogenic	reviewed by expert panel
1342210	NM_000261.2(MYOC):c.736G>A (p.Gly246Arg)	MYOC	Likely pathogenic	reviewed by expert panel
1342962	NM_000261.2(MYOC):c.1087G>A (p.Ala363Thr)	MYOC	Likely pathogenic	reviewed by expert panel
1342963	NM_000261.2(MYOC):c.1100_1103delinsT (p.Gly367_Gln368delinsVal)	MYOC	Likely pathogenic	reviewed by expert panel
1342964	NM_000261.2(MYOC):c.1139A>G (p.Asp380Gly)	MYOC	Likely pathogenic	reviewed by expert panel
1342965	NM_000261.2(MYOC):c.1138G>T (p.Asp380Tyr)	MYOC	Likely pathogenic	reviewed by expert panel
1342967	NM_000261.2(MYOC):c.761C>T (p.Pro254Leu)	MYOC	Likely pathogenic	reviewed by expert panel
1342969	NM_000261.2(MYOC):c.967G>A (p.Glu323Lys)	MYOC	Likely pathogenic	reviewed by expert panel
1686782	NM_000261.2(MYOC):c.1276G>T (p.Val426Phe)	MYOC	Likely pathogenic	reviewed by expert panel
1686788	NM_000261.2(MYOC):c.814C>G (p.Arg272Gly)	MYOC	Likely pathogenic	reviewed by expert panel
1686789	NM_000261.2(MYOC):c.1442C>T (p.Pro481Leu)	MYOC	Likely pathogenic	reviewed by expert panel
1686792	NM_000261.2(MYOC):c.1495A>T (p.Ile499Phe)	MYOC	Likely pathogenic	reviewed by expert panel
1686793	NM_000261.2(MYOC):c.1496T>G (p.Ile499Ser)	MYOC	Likely pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 70 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
MYOC	MYOC	GWAS, Orphanet

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
RAMP2	Moderate	Autosomal dominant	open-angle glaucoma	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYOC	Orphanet:98976	Congenital glaucoma
MYOC	Orphanet:98977	Juvenile glaucoma
RORA	Orphanet:528084	Non-specific syndromic intellectual disability
RPE65	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
RPE65	Orphanet:65	Leber congenital amaurosis
RPE65	Orphanet:791	Retinitis pigmentosa
SALL1	Orphanet:857	Townes-Brocks syndrome
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
SEMA3C	Orphanet:388	Hirschsprung disease
SIX1	Orphanet:107	BOR syndrome
SIX1	Orphanet:52429	Branchiootic syndrome
SIX1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
SIX6	Orphanet:35612	Nanophthalmos
SIX6	Orphanet:435930	Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome
SIX6	Orphanet:98938	Colobomatous microphthalmia
TCF12	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
TCF12	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
TFAP2B	Orphanet:46627	Char syndrome
TFAP2B	Orphanet:466729	Familial patent arterial duct
TGFBR3	Orphanet:231160	Familial cerebral saccular aneurysm
IKZF2	Orphanet:697389	Combined immunodeficiency due to HELIOS deficiency
IKZF2	Orphanet:699599	ICHAD syndrome
CACNA2D1	Orphanet:130	Brugada syndrome
CACNA2D1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA2D1	Orphanet:51083	Congenital short QT syndrome
CAV1	Orphanet:220393	Diffuse cutaneous systemic sclerosis
CAV1	Orphanet:220402	Limited cutaneous systemic sclerosis
CAV1	Orphanet:275777	Heritable pulmonary arterial hypertension
CAV1	Orphanet:696206	Congenital generalized lipodystrophy type 3
ANKH	Orphanet:1416	Familial calcium pyrophosphate deposition
ANKH	Orphanet:1522	Craniometaphyseal dysplasia
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma
ZFPM2	Orphanet:2140	Congenital diaphragmatic hernia
ZFPM2	Orphanet:251510	46,XY partial gonadal dysgenesis
ZFPM2	Orphanet:3303	Tetralogy of Fallot
TRIOBP	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
ADAMTS18	Orphanet:369970	Microcornea-myopic chorioretinal atrophy-telecanthus syndrome
PLCE1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
CDH11	Orphanet:1299	Branchioskeletogenital syndrome
SPRED2	Orphanet:648	Noonan syndrome
CDKN2B	Orphanet:618	Familial melanoma
CDKN2B	Orphanet:652	Multiple endocrine neoplasia type 1
TXNRD2	Orphanet:154	Familial isolated dilated cardiomyopathy
TXNRD2	Orphanet:361	Familial glucocorticoid deficiency
TMCO1	Orphanet:1394	Cerebrofaciothoracic dysplasia

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	73
gwas_and_clinvar	1
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYOC	HGNC:7610	ENSG00000034971	Q99972	Myocilin	gwas,clinvar
RAMP2	HGNC:9844	ENSG00000131477	O60895	Receptor activity-modifying protein 2	gencc
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gwas
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	gwas
SALL1	HGNC:10524	ENSG00000103449	Q9NSC2	Sal-like protein 1	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
SEMA3C	HGNC:10725	ENSG00000075223	Q99985	Semaphorin-3C	gwas
SRSF3	HGNC:10785	ENSG00000112081	P84103	Serine/arginine-rich splicing factor 3	gwas
BNIP1	HGNC:1082	ENSG00000113734	Q12981	Vesicle transport protein SEC20	gwas
SIX1	HGNC:10887	ENSG00000126778	Q15475	Homeobox protein SIX1	gwas
SIX6	HGNC:10892	ENSG00000184302	O95475	Homeobox protein SIX6	gwas
ZNRD2	HGNC:11328	ENSG00000173465	O60232	Protein ZNRD2	gwas
TCF12	HGNC:11623	ENSG00000140262	Q99081	Transcription factor 12	gwas
CRIPTO3	HGNC:11703	ENSG00000225366	P51864	Protein CRIPTO3	gwas
TFAP2B	HGNC:11743	ENSG00000008196	Q92481	Transcription factor AP-2-beta	gwas
TGFBR3	HGNC:11774	ENSG00000069702	Q03167	Transforming growth factor beta receptor type 3	gwas
IKZF2	HGNC:13177	ENSG00000030419	Q9UKS7	Zinc finger protein Helios	gwas
SLC6A15	HGNC:13621	ENSG00000072041	Q9H2J7	Sodium-dependent neutral amino acid transporter B(0)AT2	gwas
CACNA2D1	HGNC:1399	ENSG00000153956	P54289	Voltage-dependent calcium channel subunit alpha-2/delta-1	gwas
ARHGEF12	HGNC:14193	ENSG00000196914	Q9NZN5	Rho guanine nucleotide exchange factor 12	gwas
CALD1	HGNC:1441	ENSG00000122786	Q05682	Caldesmon	gwas
CAV1	HGNC:1527	ENSG00000105974	Q03135	Caveolin-1	gwas
CAV2	HGNC:1528	ENSG00000105971	P51636	Caveolin-2	gwas
ANKH	HGNC:15492	ENSG00000154122	Q9HCJ1	Mineralization regulator ANKH	gwas
CTTNBP2	HGNC:15679	ENSG00000077063	Q8WZ74	Cortactin-binding protein 2	gwas
SVEP1	HGNC:15985	ENSG00000165124	Q4LDE5	Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1	gwas
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	gwas
ZFPM2	HGNC:16700	ENSG00000169946	Q8WW38	Zinc finger protein ZFPM2	gwas
FBXO32	HGNC:16731	ENSG00000156804	Q969P5	F-box only protein 32	gwas
TRIOBP	HGNC:17009	ENSG00000100106	Q9H2D6	TRIO and F-actin-binding protein	gwas
ADAMTS18	HGNC:17110	ENSG00000140873	Q8TE60	A disintegrin and metalloproteinase with thrombospondin motifs 18	gwas
SEPTIN7	HGNC:1717	ENSG00000122545	Q16181	Septin-7	gwas
PLCE1	HGNC:17175	ENSG00000138193	Q9P212	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	gwas
CDC7	HGNC:1745	ENSG00000097046	O00311	Cell division cycle 7-related protein kinase	gwas
CDH11	HGNC:1750	ENSG00000140937	P55287	Cadherin-11	gwas
SPRED2	HGNC:17722	ENSG00000198369	Q7Z698	Sprouty-related, EVH1 domain-containing protein 2	gwas
SMG6	HGNC:17809	ENSG00000070366	Q86US8	Telomerase-binding protein EST1A	gwas
CDKN2B	HGNC:1788	ENSG00000147883	P42772	Cyclin-dependent kinase 4 inhibitor B	gwas
TXNRD2	HGNC:18155	ENSG00000184470	Q9NNW7	Thioredoxin reductase 2, mitochondrial	gwas
TMCO1	HGNC:18188	ENSG00000143183	Q9UM00	Calcium load-activated calcium channel	gwas
FMNL2	HGNC:18267	ENSG00000157827	Q96PY5	Formin-like protein 2	gwas
BICC1	HGNC:19351	ENSG00000122870	Q9H694	Protein bicaudal C homolog 1	gwas
FAM13A	HGNC:19367	ENSG00000138640	O94988	Protein FAM13A	gwas
C14orf39	HGNC:19849	ENSG00000179008	Q8N1H7	Protein SIX6OS1	gwas
TRAPPC3	HGNC:19942	ENSG00000054116	O43617	Trafficking protein particle complex subunit 3	gwas
AREL1	HGNC:20363	ENSG00000119682	O15033	Apoptosis-resistant E3 ubiquitin protein ligase 1	gwas
LSM8	HGNC:20471	ENSG00000128534	O95777	U6 snRNA-associated Sm-like protein LSm8	gwas
CYP26C1	HGNC:20577	ENSG00000187553	Q6V0L0	Cytochrome P450 26C1	gwas
TMEM181	HGNC:20958	ENSG00000146433	Q9P2C4	Transmembrane protein 181	gwas
ANTXR1	HGNC:21014	ENSG00000169604	Q9H6X2	Anthrax toxin receptor 1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYOC	Myocilin	Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration.
RAMP2	Receptor activity-modifying protein 2	Accessory protein that interacts with and modulates the function of G-protein coupled receptors including calcitonin gene-related peptide type 1 receptor (CALCRL) and calcitonin receptor (CALCR).
RORA	Nuclear receptor ROR-alpha	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
SALL1	Sal-like protein 1	Transcriptional repressor involved in organogenesis.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
SEMA3C	Semaphorin-3C	Binds to plexin family members and plays an important role in the regulation of developmental processes.
SRSF3	Serine/arginine-rich splicing factor 3	Splicing factor, which binds the consensus motif 5’-C[ACU][AU]C[ACU][AC]C-3’ within pre-mRNA and promotes specific exons inclusion during alternative splicing.
BNIP1	Vesicle transport protein SEC20	As part of a SNARE complex may be involved in endoplasmic reticulum membranes fusion and be required for the maintenance of endoplasmic reticulum organization.
SIX1	Homeobox protein SIX1	Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development.
SIX6	Homeobox protein SIX6	May be involved in eye development.
ZNRD2	Protein ZNRD2	Might play a role in mitosis.
TCF12	Transcription factor 12	Transcriptional regulator.
CRIPTO3	Protein CRIPTO3	Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm.
TFAP2B	Transcription factor AP-2-beta	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
TGFBR3	Transforming growth factor beta receptor type 3	Cell surface receptor that regulates diverse cellular processes including cell proliferation, differentiation, migration, and apoptosis.
IKZF2	Zinc finger protein Helios	Transcription factor, which stabilizes the noninflammatory phenotype of regulatory T cells (Tregs).
SLC6A15	Sodium-dependent neutral amino acid transporter B(0)AT2	Functions as a sodium-dependent neutral amino acid transporter.
CACNA2D1	Voltage-dependent calcium channel subunit alpha-2/delta-1	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
ARHGEF12	Rho guanine nucleotide exchange factor 12	Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13.
CALD1	Caldesmon	Actin- and myosin-binding protein implicated in the regulation of actomyosin interactions in smooth muscle and nonmuscle cells (could act as a bridge between myosin and actin filaments).
CAV1	Caveolin-1	May act as a scaffolding protein within caveolar membranes.
CAV2	Caveolin-2	May act as a scaffolding protein within caveolar membranes.
ANKH	Mineralization regulator ANKH	Transports adenosine triphosphate (ATP) and possibly other nucleoside triphosphates (NTPs) from cytosol to the extracellular space.
CTTNBP2	Cortactin-binding protein 2	Regulates the dendritic spine distribution of CTTN/cortactin in hippocampal neurons, and thus controls dendritic spinogenesis and dendritic spine maintenance.
SVEP1	Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1	Required for morphological development, cell alignment and migration of lymphatic endothelial cells during embryonic development, potentially via modulation of ANGPT2-TIE1 signaling and subsequent activation of FOXC2 transcription.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
ZFPM2	Zinc finger protein ZFPM2	Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis.
FBXO32	F-box only protein 32	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
TRIOBP	TRIO and F-actin-binding protein	Regulates actin cytoskeletal organization, cell spreading and cell contraction by directly binding and stabilizing filamentous F-actin and prevents its depolymerization.
SEPTIN7	Septin-7	Filament-forming cytoskeletal GTPase.
PLCE1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
CDC7	Cell division cycle 7-related protein kinase	Kinase involved in initiation of DNA replication.
CDH11	Cadherin-11	Cadherins are calcium-dependent cell adhesion proteins.
SPRED2	Sprouty-related, EVH1 domain-containing protein 2	Negatively regulates Ras signaling pathways and downstream activation of MAP kinases.
SMG6	Telomerase-binding protein EST1A	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.
CDKN2B	Cyclin-dependent kinase 4 inhibitor B	Interacts strongly with CDK4 and CDK6.
TXNRD2	Thioredoxin reductase 2, mitochondrial	Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis.
TMCO1	Calcium load-activated calcium channel	Endoplasmic reticulum (ER) calcium-selective channel preventing intracellular Ca2(+) stores from overfilling and maintaining calcium homeostasis in the ER.
FMNL2	Formin-like protein 2	Plays a role in the regulation of cell morphology and cytoskeletal organization.
BICC1	Protein bicaudal C homolog 1	Putative RNA-binding protein.
C14orf39	Protein SIX6OS1	Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination.
TRAPPC3	Trafficking protein particle complex subunit 3	May play a role in vesicular transport from endoplasmic reticulum to Golgi.
AREL1	Apoptosis-resistant E3 ubiquitin protein ligase 1	E3 ubiquitin-protein ligase that catalyzes ‘Lys-11’- or ‘Lys-33’-linked polyubiquitin chains, with some preference for ‘Lys-33’ linkages.
LSM8	U6 snRNA-associated Sm-like protein LSm8	Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex).
CYP26C1	Cytochrome P450 26C1	A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals.
TMEM181	Transmembrane protein 181	Mediates action of cytolethal distending toxins (CDT), which are secreted by many pathogenic bacteria.
ANTXR1	Anthrax toxin receptor 1	Plays a role in cell attachment and migration.
FAM120B	Constitutive coactivator of peroxisome proliferator-activated receptor gamma	Functions as a transactivator of PPARG and ESR1.
RSPO1	R-spondin-1	Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors.

Protein-family classification

Druggable: 15 · Difficult: 15 · Unknown: 45 · Druggable fraction: 0.2

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
Nuclear receptor	1	5.2×	0.487
Complement	1	3.6×	0.487
Antibody/Immunoglobulin	4	1.6×	0.487
Scaffold/PPI	6	1.4×	0.487
Other/Unknown	45	1.1×	0.487
Protease	3	1.5×	0.505
Kinase	3	1.1×	0.635
Transcription factor	9	1.0×	0.635
Enzyme (other)	3	0.5×	0.955

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYOC	Other/Unknown	no		Olfac-like_dom, Olfactomedin-like_domain
RAMP2	Other/Unknown	no		RAMP, RAMP_sf
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase
SALL1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
SEMA3C	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
SRSF3	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
BNIP1	Other/Unknown	no		Sec20, Sec20_C
SIX1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
SIX6	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
ZNRD2	Other/Unknown	no		ZNRD2_N, UPF0148_domain
TCF12	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
CRIPTO3	Other/Unknown	no		EGF, Cripto, Cryptic/Cripto_CFC-dom
TFAP2B	Transcription factor	no		TF_AP2, TF_AP2_beta, TF_AP2_C
TGFBR3	Other/Unknown	no		ZP_dom, ZP_dom_CS, ZP-C_dom
IKZF2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF
SLC6A15	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf
CACNA2D1	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
ARHGEF12	Scaffold/PPI	no		DH_dom, GDS_CDC24_CS, PDZ
CALD1	Other/Unknown	no		Caldesmon, Caldesmon_LSP
CAV1	Other/Unknown	no		Caveolin, Caveolin_CS
CAV2	Other/Unknown	no		Caveolin, Caveolin_CS
ANKH	Other/Unknown	no		ANKH
CTTNBP2	Scaffold/PPI	no		Ankyrin_rpt, Cortactin-binding_p2_N, Ankyrin_rpt-contain_sf
SVEP1	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
ZFPM2	Transcription factor	no		Znf_C2H2_type, Znf_CCHC_FOG, Znf_C2H2_sf
FBXO32	Other/Unknown	no		F-box-like_dom_sf, FBX25/32
TRIOBP	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, M-RIP_PH
ADAMTS18	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
SEPTIN7	Other/Unknown	no		Septin7, Septin, P-loop_NTPase
PLCE1	Enzyme (other)	yes	3.1.4.11	C2_dom, RA_dom, PLipase_C_PInositol-sp_X_dom
CDC7	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CDH11	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
SPRED2	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf
SMG6	Other/Unknown	no		PIN_dom, TPR-like_helical_dom_sf, DNA/RNA-bd_Est1-type
CDKN2B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
TXNRD2	Enzyme (other)	yes	1.8.1.9	Pyr_nuc-diS_OxRdtase, Pyr_nucl-diS_OxRdtase_dimer, Thioredoxin/glutathione_Rdtase
TMCO1	Other/Unknown	no		EMC3/TMCO1, TMCO1
FMNL2	Other/Unknown	no		FH3_dom, GTPase-bd, ARM-like
BICC1	Other/Unknown	no		SAM, KH_dom, KH_dom_type_1
FAM13A	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, FAM13
C14orf39	Other/Unknown	no		SIX6OS1
TRAPPC3	Other/Unknown	no		TRAPP_component, Bet3, NO_sig/Golgi_transp_ligand-bd
AREL1	Antibody/Immunoglobulin	yes	2.3.2.26	HECT_dom, Ig-like_fold, Ig_E-set
LSM8	Other/Unknown	no		Sm_dom_euk/arc, LSM_dom_sf, Lsm8
CYP26C1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CS
TMEM181	Other/Unknown	no		TMEM181, WLS-like_TM, TMEM181_GOLD
ANTXR1	Other/Unknown	no		VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel

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	10
calcaneal tendon	8
ventricular zone	7
primordial germ cell in gonad	7
cortical plate	7
secondary oocyte	5
right testis	5
oocyte	4
lower lobe of lung	4
tibia	4
corpus callosum	4
stromal cell of endometrium	4
upper leg skin	3
inferior vagus X ganglion	3
colonic epithelium	3
biceps brachii	3
skeletal muscle tissue of biceps brachii	3
apex of heart	3
periodontal ligament	3
metanephric glomerulus	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYOC	201	tissue_specific	marker	calcaneal tendon, mucosa of stomach, esophagogastric junction muscularis propria
RAMP2	211	ubiquitous	marker	right lung, mucosa of stomach, omental fat pad
RORA	284	ubiquitous	marker	upper leg skin, lateral nuclear group of thalamus, skin of hip
RPE65	92	tissue_specific	marker	pigmented layer of retina, retina, male germ line stem cell (sensu Vertebrata) in testis
SALL1	195	broad	marker	ventricular zone, inferior vagus X ganglion, renal medulla
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
SEMA3C	289	ubiquitous	marker	mammary duct, synovial joint, calcaneal tendon
SRSF3	295	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
BNIP1	226	ubiquitous	marker	secondary oocyte, oocyte, diaphragm
SIX1	188	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, parotid gland
SIX6	34	tissue_specific	marker	adenohypophysis, pituitary gland, cranial nerve II
ZNRD2	189	ubiquitous	marker	body of pancreas, apex of heart, hindlimb stylopod muscle
TCF12	295	ubiquitous	marker	periodontal ligament, ventricular zone, ganglionic eminence
CRIPTO3	23		marker	male germ line stem cell (sensu Vertebrata) in testis, vastus lateralis, primordial germ cell in gonad
TFAP2B	128	broad	marker	corpus epididymis, cauda epididymis, oocyte
TGFBR3	288	ubiquitous	marker	renal glomerulus, metanephric glomerulus, synovial joint
IKZF2	232	ubiquitous	marker	thymus, palpebral conjunctiva, amniotic fluid
SLC6A15	204	ubiquitous	marker	cortical plate, pigmented layer of retina, retina
CACNA2D1	261	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis
ARHGEF12	288	ubiquitous	marker	upper leg skin, visceral pleura, heart right ventricle
CALD1	293	ubiquitous	marker	blood vessel layer, saphenous vein, cauda epididymis
CAV1	287	ubiquitous	marker	parietal pleura, lower lobe of lung, pleura
CAV2	290	ubiquitous	marker	lower lobe of lung, heart right ventricle, blood vessel layer
ANKH	273	ubiquitous	marker	tibia, parotid gland, inferior vagus X ganglion
CTTNBP2	230	broad	marker	cortical plate, corpus callosum, embryo
SVEP1	225	broad	marker	pericardium, lower lobe of lung, placenta
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
ZFPM2	239	ubiquitous	marker	skeletal muscle tissue of biceps brachii, germinal epithelium of ovary, biceps brachii
FBXO32	257	ubiquitous	marker	cardiac muscle of right atrium, deltoid, tibialis anterior
TRIOBP	289	ubiquitous	marker	lower lobe of lung, cervix squamous epithelium, apex of heart

Protein interactions among cohort

Intra-cohort edges: 22.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAV1	6,673
CHEK2	4,795
PNPT1	3,741
TXNRD2	3,712
CDKN2B	3,431
ATXN2	3,360
CDC7	2,963
EXOC2	2,587
LSM8	2,541
FBXO32	2,519

Intra-cohort edges

A	B	Sources
AFAP1	FNDC3B	string_interaction
AFAP1	SIX6	string_interaction
AFAP1	TMCO1	string_interaction
CAV1	CAV2	biogrid_interaction, intact, string_interaction
CAV1	SLC6A15	biogrid_interaction
CAV1	SPRED2	string_interaction
CAV1	TMCO1	string_interaction
CAV2	TMCO1	string_interaction
CDC7	CHEK2	string_interaction
EXOC2	EXOC6	biogrid_interaction, intact, string_interaction
FAM13A	TBCCD1	biogrid_interaction, intact
FNDC3B	POU6F2	intact
FNDC3B	SIX6	string_interaction
FNDC3B	TMCO1	string_interaction
MYOC	TMCO1	string_interaction
POU6F2	SIX1	intact
RAMP2	SVEP1	string_interaction
SALL1	SIX1	string_interaction
SIX1	TMCO1	string_interaction
SIX6	TMCO1	string_interaction
TBCCD1	ZNRD2	intact
TMTC2	ZNRD2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHEK2	O96017	38
CACNA2D1	P54289	30
MYOC	Q99972	24
LSM8	O95777	20
RSPO1	Q2MKA7	12
CRYGS	P22914	12
PNPT1	Q8TCS8	11
RAMP2	O60895	10
CDC7	O00311	9
SEPTIN7	Q16181	8
IKZF2	Q9UKS7	7
CELF2	O95319	7
SMG6	Q86US8	5
ANTXR1	Q9H6X2	5
ARHGEF12	Q9NZN5	4
TRAPPC3	O43617	4
EFHC2	Q5JST6	4
RORA	P35398	3
SRSF3	P84103	3
PLCE1	Q9P212	3
BICC1	Q9H694	3
TCF12	Q99081	2
SPRED2	Q7Z698	2
AREL1	O15033	2
MPP7	Q5T2T1	2
ATXN2	Q99700	1
SIX1	Q15475	1
ZNRD2	O60232	1
TFAP2B	Q92481	1
TGFBR3	Q03167	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPE65	Q16518	95.34
ACOXL	Q9NUZ1	92.00
TMTC2	Q8N394	90.57
CDKN2B	P42772	90.12
CYP26A1	O43174	89.64
CYP26C1	Q6V0L0	89.34
TBCCD1	Q9NVR7	86.97
SEMA3C	Q99985	85.69
ANKH	Q9HCJ1	84.57
EXOC6	Q8TAG9	82.02
SIX6	O95475	81.68
BNIP1	Q12981	80.86
EXOC2	Q96KP1	80.82
ADAMTS8	Q9UP79	80.22
SLC6A15	Q9H2J7	80.15
FBXO32	Q969P5	80.15
TMEM181	Q9P2C4	78.28
CAV2	P51636	78.26
CDH11	P55287	77.65
FNDC3B	Q53EP0	75.78
ADAMTS18	Q8TE60	73.83
AGBL2	Q5U5Z8	72.22
FAM120B	Q96EK7	71.92
AFAP1	Q8N556	67.09
CRIPTO3	P51864	66.63
CALD1	Q05682	65.68
FAM13A	O94988	61.00
C14orf39	Q8N1H7	58.97
CTTNBP2	Q8WZ74	58.83
ZNF280D	Q6N043	56.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 441. Enrichment computed across 159 evidence-associated genes (92 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 92 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Kidney development	3	26.6×	0.076	SALL1, SIX1, MECOM
Vitamins	2	41.4×	0.099	CYP26C1, CYP26A1
Formation of the ureteric bud	3	16.2×	0.099	SALL1, SIX1, FOXC1
TGFBR3 expression	3	14.9×	0.099	TCF12, TGFBR3, MOV10
Signaling by TGFB family members	5	6.3×	0.099	TGFBR3, CDKN2B, LTBP3, SMAD6, MOV10
Signal Transduction	19	2.1×	0.099	TGFBR3, ARHGEF12, CAV1, CAV2, SEPTIN7, SPRED2, CDKN2B, RSPO1 (+11 more)
Regulation of CDH11 mRNA translation by microRNAs	2	27.6×	0.109	CDH11, MOV10
Signaling by BMP	3	11.6×	0.109	TGFBR3, CHRDL1, SMAD6
MAPK family signaling cascades	5	5.6×	0.109	SEPTIN7, SPRED2, ANGPT1, IQGAP1, MOV10
Oncogene Induced Senescence	3	10.9×	0.111	CDKN2B, ETS1, MOV10
Defective B3GALTL causes PpS	3	10.1×	0.121	ADAMTS18, THSD7A, ADAMTS8
O-glycosylation of TSR domain-containing proteins	3	9.8×	0.121	ADAMTS18, THSD7A, ADAMTS8
RHOC GTPase cycle	4	6.4×	0.121	ARHGEF12, CAV1, FMNL2, IQGAP1
Cell-Cell communication	4	6.0×	0.141	CDH11, CADM2, IQGAP1, MOV10
Defective PMM2 causes PMM2-CDG	1	124.1×	0.142	PMM2
Defective CYP26C1 causes FFDD4	1	124.1×	0.142	CYP26C1
Signaling by FGFR1	2	17.7×	0.142	TGFBR3, SPRED2
Regulation of CDH11 Expression and Function	2	17.7×	0.142	CDH11, MOV10
Peroxisomal lipid metabolism	2	14.6×	0.142	ACOXL, NUDT7
Regulation of Homotypic Cell-Cell Adhesion	2	14.6×	0.142	CDH11, MOV10
Regulation of Expression and Function of Type II Classical Cadherins	2	14.6×	0.142	CDH11, MOV10
Adherens junctions interactions	3	8.1×	0.142	CDH11, CADM2, MOV10
Cell-cell junction organization	3	8.1×	0.142	CDH11, CADM2, MOV10
RHOA GTPase cycle	5	4.1×	0.142	ARHGEF12, CAV1, FAM13A, IQGAP1, ARHGEF3
RNA Polymerase II Transcription	10	2.5×	0.142	RORA, SRSF3, TFAP2B, CAV1, CDC7, CDKN2B, GTF2E2, SMAD6 (+2 more)
Diseases associated with O-glycosylation of proteins	3	7.0×	0.150	ADAMTS18, THSD7A, ADAMTS8
Signaling by TGF-beta Receptor Complex	3	6.5×	0.177	TGFBR3, CDKN2B, LTBP3
VxPx cargo-targeting to cilium	2	11.3×	0.196	EXOC6, EXOC2
Cell junction organization	3	6.1×	0.196	CDH11, CADM2, MOV10
Signaling by Nuclear Receptors	4	4.4×	0.196	CAV1, CAV2, ABCA1, MOV10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 133 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
caveola assembly	3	47.5×	0.009	CAV1, CAV2, IQGAP1
negative regulation of chondrocyte differentiation	4	20.3×	0.009	EFEMP1, LTBP3, PTHLH, RARB
outflow tract septum morphogenesis	4	19.5×	0.009	SEMA3C, ZFPM2, SMAD6, RARB
ureteric bud development	5	17.1×	0.009	SALL1, SIX1, FOXC1, SMAD6, RARB
eye development	5	13.2×	0.009	SIX6, ADAMTS18, CHRDL1, FOXC1, MEIS1
kidney development	7	7.4×	0.009	SALL1, SIX1, TFAP2B, BICC1, CYP26A1, FOXC1, PKHD1
cerebellar granule cell precursor proliferation	3	34.6×	0.011	RORA, PSMG1, RERE
positive regulation of transcription by RNA polymerase II	22	2.5×	0.011	RORA, SALL1, SIX1, TCF12, TFAP2B, IKZF2, ZFPM2, GLIS1 (+14 more)
pulmonary myocardium development	2	84.5×	0.018	SEMA3C, PITX2
regulation of membrane repolarization during action potential	2	84.5×	0.018	CACNA2D1, CAV1
negative regulation of phospholipase C/protein kinase C signal transduction	2	84.5×	0.018	DGKD, DGKG
cell differentiation	14	3.1×	0.018	TCF12, CAV1, CAV2, ZFPM2, SEPTIN7, THSD7A, GLIS1, CHRDL1 (+6 more)
embryonic digestive tract development	3	22.4×	0.023	SALL1, FOXF2, RARB
ossification	5	8.6×	0.023	CDH11, TMCO1, DDR2, CHRDL1, GPM6B
angiogenesis	9	4.2×	0.023	RORA, CAV1, THSD7A, FOXC1, ANGPT1, KLF5, MEIS1, NDP (+1 more)
response to laminar fluid shear stress	2	63.4×	0.024	ABCA1, SMAD6
negative regulation of extracellular matrix assembly	2	63.4×	0.024	TGFBR3, ANTXR1
retinoic acid catabolic process	2	50.7×	0.034	CYP26C1, CYP26A1
Tie signaling pathway	2	50.7×	0.034	SVEP1, ANGPT1
regulation of entry of bacterium into host cell	2	50.7×	0.034	CAV1, EXOC2
cell-substrate adhesion	3	17.3×	0.036	CDH11, ANGPT1, SMAD6
vitamin metabolic process	2	42.2×	0.043	CYP26C1, CYP26A1
regulation of skeletal muscle satellite cell proliferation	2	42.2×	0.043	SIX1, ANGPT1
ventricular cardiac muscle tissue morphogenesis	3	15.8×	0.043	TGFBR3, COL11A1, FOXC1
transforming growth factor beta receptor signaling pathway	5	6.0×	0.066	TGFBR3, CAV2, CDKN2B, LTBP3, NDP
visual perception	7	4.2×	0.066	RPE65, SIX6, POU6F2, COL11A1, CRYGS, EFEMP1, NDP
maintenance of lens transparency	2	31.7×	0.070	FOXC1, APBB2
vasculogenesis	4	7.7×	0.074	CAV1, ZFPM2, PITX2, RAMP2
regulation of fatty acid metabolic process	2	28.2×	0.081	CAV1, PRKAG2
obsolete vesicle tethering involved in exocytosis	2	28.2×	0.081	EXOC6, EXOC2

Therapeutics

Drugs indicated for this disease

10 approved, 7 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Bimatoprost	Approved (phase 4)
Brinzolamide	Approved (phase 4)
Latanoprost	Approved (phase 4)
Latanoprostene Bunod	Approved (phase 4)
Methazolamide	Approved (phase 4)
Omidenepag Isopropyl	Approved (phase 4)
Pilocarpine	Approved (phase 4)
Tafluprost	Approved (phase 4)
Timolol	Approved (phase 4)
Travoprost	Approved (phase 4)
Betaxolol	Phase 3 (in late-stage trials)
Citicoline	Phase 3 (in late-stage trials)
Dorzolamide	Phase 3 (in late-stage trials)
Memantine	Phase 3 (in late-stage trials)
Ofloxacin	Phase 3 (in late-stage trials)
Prednisolone	Phase 3 (in late-stage trials)
Trabodenoson	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Anecortave Acetate, Bimatoprost Grenod, Brimonidine, Ginkgo, Mitomycin, Niacinamide, Sodium Chloride.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 7 · Phased (≥1): 10 · Undrugged: 65

Druggability breadth: 56 of 159 evidence-associated genes (35%) 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
RAMP2	PRAMLINTIDE
RORA	TRETINOIN
SLC6A15	LORATADINE
CACNA2D1	PREGABALIN
CHEK2	NERATINIB
CYP26A1	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHEK2	30	4
CDC7	7	2
CACNA2D1	5	4
CYP26A1	5	4
TXNRD2	3	3
RAMP2	2	4
RORA	2	4
SRSF3	1	2
SLC6A15	1	4
CALD1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRAMLINTIDE	4	RAMP2
TRETINOIN	4	RORA
LORATADINE	4	SLC6A15
PREGABALIN	4	CACNA2D1
GABAPENTIN	4	CACNA2D1
NIMODIPINE	4	CACNA2D1
TACRINE	4	CACNA2D1
NERATINIB	4	CHEK2
BOSUTINIB	4	CHEK2
BRIGATINIB	4	CHEK2
SUNITINIB	4	CHEK2
GEFITINIB	4	CHEK2
BEXAROTENE	4	CYP26A1
KETOCONAZOLE	4	CYP26A1
TAMIBAROTENE	4	CYP26A1
CAGRILINTIDE	3	RAMP2
FASUDIL	3	CHEK2
CEDIRANIB	3	CHEK2
DOVITINIB	3	CHEK2
LESTAURTINIB	3	CHEK2
RUBOXISTAURIN	3	CHEK2
CURCUMIN	3	TXNRD2
MOLIBRESIB	2	CALD1, CDC7, SRSF3
Z160	2	CACNA2D1
DORAMAPIMOD	2	CHEK2
FORETINIB	2	CHEK2
SU-014813	2	CHEK2
CENISERTIB	2	CDC7, CHEK2
ILORASERTIB	2	CHEK2
CEP-11981	2	CHEK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
CHEK2	690	Binding:687, Functional:2, ADMET:1
CDC7	222	Binding:221, Functional:1
RORA	115	Binding:111, Functional:3, Unclassified:1
TXNRD2	91	Binding:76, Functional:15
CACNA2D1	47	Binding:45, ADMET:1, Toxicity:1
CYP26A1	35	Binding:28, Functional:6, ADMET:1
IKZF2	26	Binding:26
SIX1	12	Binding:12
ARHGEF12	11	Binding:11
RAMP2	7	Functional:4, Binding:3
SRSF3	7	Binding:7
CALD1	6	Binding:6
ATXN2	5	Binding:3, Functional:2
SLC6A15	5	Binding:5
CAV1	5	Binding:5
MYOC	4	Binding:4
AGBL2	3	Binding:3
LSM8	2	Binding:2
ZNRD2	1	Binding:1
TCF12	1	Binding:1
SEPTIN7	1	Binding:1
TMCO1	1	Binding:1
CELF2	1	Binding:1
ZNF280D	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
PLCE1	3.1.4.11	phosphoinositide phospholipase C
CDC7	2.7.11.1	non-specific serine/threonine protein kinase
TXNRD2	1.8.1.9	thioredoxin-disulfide reductase (NADPH)
AREL1	2.3.2.26	HECT-type E3 ubiquitin transferase
PNPT1	2.7.7.8	polyribonucleotide nucleotidyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RORA	115
CHEK2	690
CDC7	222

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)
PRAMLINTIDE	4	RAMP2
TRETINOIN	4	RORA
LORATADINE	4	SLC6A15
PREGABALIN	4	CACNA2D1
GABAPENTIN	4	CACNA2D1
NIMODIPINE	4	CACNA2D1
TACRINE	4	CACNA2D1
NERATINIB	4	CHEK2
BOSUTINIB	4	CHEK2
BRIGATINIB	4	CHEK2
SUNITINIB	4	CHEK2
GEFITINIB	4	CHEK2
BEXAROTENE	4	CYP26A1
KETOCONAZOLE	4	CYP26A1
TAMIBAROTENE	4	CYP26A1
CAGRILINTIDE	3	RAMP2
FASUDIL	3	CHEK2
CEDIRANIB	3	CHEK2
DOVITINIB	3	CHEK2
LESTAURTINIB	3	CHEK2
RUBOXISTAURIN	3	CHEK2
CURCUMIN	3	TXNRD2
MOLIBRESIB	2	CALD1, CDC7, SRSF3
Z160	2	CACNA2D1
DORAMAPIMOD	2	CHEK2
FORETINIB	2	CHEK2
SU-014813	2	CHEK2
CENISERTIB	2	CDC7, CHEK2
ILORASERTIB	2	CHEK2
CEP-11981	2	CHEK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	RAMP2, RORA, SLC6A15, CACNA2D1, CHEK2, CYP26A1
B	Phased (≥1) drug, not yet approved	4	SRSF3, CALD1, CDC7, TXNRD2
C	Druggable family + PDB, no drug	3	PLCE1, AREL1, MPP7
D	Druggable family + AlphaFold only, no drug	8	RPE65, SEMA3C, SVEP1, ADAMTS18, ADAMTS8, FNDC3B, EXOC2, AGBL2
E	Difficult family or no structure, no drug	54	MYOC, SALL1, ATXN2, BNIP1, SIX1, SIX6, ZNRD2, TCF12, CRIPTO3, TFAP2B (+44 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYOC	4	—
RPE65	0	—
SALL1	0	—
ATXN2	5	—
SEMA3C	0	—
BNIP1	0	—
SIX1	12	—
SIX6	0	—
ZNRD2	1	—
TCF12	1	—
CRIPTO3	0	—
TFAP2B	0	—
TGFBR3	0	—
IKZF2	26	—
ARHGEF12	11	—
CAV1	5	—
CAV2	0	—
ANKH	0	—
CTTNBP2	0	—
SVEP1	0	—
ZFPM2	0	—
FBXO32	0	—
TRIOBP	0	—
ADAMTS18	0	—
SEPTIN7	1	—
PLCE1	0	—
CDH11	0	—
SPRED2	0	—
SMG6	0	—
CDKN2B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 618.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	302
PHASE3	101
PHASE4	86
PHASE2	81
PHASE1	22
PHASE1/PHASE2	18
PHASE2/PHASE3	6
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04007276	PHASE4	NOT_YET_RECRUITING	The Effect of Lumify™ on Ocular Redness, Intraocular Pressure, and Eyelid Position in Glaucoma Patients
NCT05821855	PHASE4	ACTIVE_NOT_RECRUITING	A Study to Evaluate Adverse Events and Change in Disease Activity With the XEN45 Glaucoma Treatment System Implantation In Adult Participants With Open-Angle Glaucoma in China
NCT06498440	PHASE4	NOT_YET_RECRUITING	Efficacy of NSAID vs. Steroid-NSAID Combo Post-Selective Laser Trabeculoplasty: Phase 4, Single-Center RCT
NCT06792422	PHASE4	RECRUITING	A Study Investigating Oral Semaglutide in People with Open-Angle Glaucoma
NCT06865144	PHASE4	RECRUITING	Effect of Rhopressa on Intraocular Pressure (IOP) in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension Post-SLT
NCT06883123	PHASE4	RECRUITING	Efficacy of Simbrinza and Rocklatan vs Cosopt and Latanoprost
NCT07048886	PHASE4	NOT_YET_RECRUITING	Rocklatan Adds Pressure Reduction After MIGS (Minimally Invasive Glaucoma Surgery)
NCT07217678	PHASE4	RECRUITING	Biomarkers of Ocular Surface Damage in the Setting of Topical Ocular Hypotensive Medication Use
NCT07228221	PHASE4	RECRUITING	Standalone iStent Infinite and iDose TR for Management of Moderate to Severe Open Angle Glaucoma
NCT07325240	PHASE4	RECRUITING	24-hour Effect of Rocklatan Compared With Latanoprost in Open Angle Glaucoma and Ocular Hypertension Patients
NCT00047606	PHASE4	TERMINATED	Phase 4 Study Comparing IOP Lowering in OAG or OH in Caucasian or Japanese Subjects C-02-32
NCT00273429	PHASE4	COMPLETED	Cosopt Versus Xalatan
NCT00273442	PHASE4	COMPLETED	Assessing Cosopt Switch Patients
NCT00273455	PHASE4	COMPLETED	Lumigan Versus Cosopt
NCT00273481	PHASE4	COMPLETED	Cosopt Versus Xalacom
NCT00300079	PHASE4	COMPLETED	Study of the Intraocular Pressure (IOP)-Lowering Efficacy of Azopt 1.0% Compared to Timolol 0.5% in Patients With Glaucoma or Ocular Hypertension
NCT00304785	PHASE4	COMPLETED	Latanoprost Versus Fotil
NCT00308945	PHASE4	COMPLETED	Influence of Prostaglandins on Ocular Blood Flow in Glaucoma Patients
NCT00326014	PHASE4	COMPLETED	A Study of the Trabecular Micro-Bypass Stent in Combination With Cataract Surgery in Open Angle Glaucoma Subjects.
NCT00326040	PHASE4	COMPLETED	A Study of the Glaukos Trabecular Micro-Bypass Stent in Refractory Open Angle Glaucoma Subjects
NCT00326079	PHASE4	UNKNOWN	A Study of the Glaukos Trabecular Micro-bypass Stent in Open Angle Glaucoma Subjects 1 Stent Versus 2
NCT00330577	PHASE4	COMPLETED	24-Hour Intraocular Pressure (IOP) And Blood Pressure Control In Glaucoma And Ocular Hypertension Patients
NCT00372827	PHASE4	COMPLETED	Study of Brinzolamide and Timolol When Added to Travoprost in Primary Open-angle Glaucoma or Ocular Hypertension
NCT00397241	PHASE4	COMPLETED	24-hour Study of Dorzolamide/Timolol and Latanoprost/Timolol Fixed Combinations
NCT00457795	PHASE4	COMPLETED	24-hour IOP-lowering Effect of Brimonidine 0.1%
NCT00471068	PHASE4	TERMINATED	Study of Travatan and Cosopt in Primary Open-Angle Glaucoma or Ocular Hypertension
NCT00508469	PHASE4	COMPLETED	Adherence Assessment With Travalert Dosing Aid
NCT00527592	PHASE4	COMPLETED	A Single Dose Comfort Comparison of Travatan Z in One Eye Versus Xalatan in the Opposite Eye in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension
NCT00538590	PHASE4	COMPLETED	Ologen Collagen Matrix Safety and Effective Comparison With Mitomycin-C(MMC) in Glaucoma Surgery
NCT00539526	PHASE4	COMPLETED	Evaluation of Hyperemia With the Use of Ocular Prostaglandin Analogues
NCT00545064	PHASE4	COMPLETED	Dry Eye Study With Cosopt® Over 8 Weeks in Patients With Open-Angle Glaucoma or Ocular Hypertension (0507A-152)(COMPLETED)
NCT00675207	PHASE4	COMPLETED	Comparison of Brimonidine Purite, Dorzolamide, and Brinzolamide as Adjunctive Therapy to Prostaglandin Analogs
NCT00698945	PHASE4	COMPLETED	Comparison of Istalol™ 0.5% QD (Timolol Maleate/Sorbitol Complex, ISTA Pharmaceutical) to Brimonidine Tartrate 0.1% BID as Adjunctive Therapy to Latanoprost 0.005% in Adults With Ocular Hypertension (OHT) or Open-Angle Glaucoma (OAG)
NCT00759239	PHASE4	COMPLETED	Phase IV Randomised Double-masked Clinical Trial: Assessing Morning Versus Evening Dosing of a Fixed Dose Combination of Travoprost 0.004% / Timolol Maleate 0.5% in Patients With Primary Open-angle Glaucoma or Ocular Hypertension
NCT00798759	PHASE4	COMPLETED	Examination of Ocular Surface Effects With Administration of Travatan Z and XALATAN
NCT00803803	PHASE4	COMPLETED	Dose, Effects and Characteristics of Pilocarpine
NCT00822055	PHASE4	COMPLETED	Comparison of the Fixed Combinations of Brimonidine/Timolol and Dorzolamide/Timolol in Subjects With Open-Angle Glaucoma or Ocular Hypertension
NCT00822081	PHASE4	COMPLETED	Comparison of the Fixed Combinations of Brimonidine/Timolol and Dorzolamide/Timolol in Subjects With Open-Angle Glaucoma or Ocular Hypertension
NCT00828906	PHASE4	COMPLETED	DuoTrav® Eye Drops As Replacement Therapy Program
NCT00887029	PHASE4	COMPLETED	A 12 Week Comparison of DuoTrav and Xalacom in Open-Angle Glaucoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TIMOLOL	4	95
LATANOPROST	4	59
TRAVOPROST	4	43
BRINZOLAMIDE	4	24
BIMATOPROST	4	21
BRIMONIDINE	4	16
DORZOLAMIDE	4	16
TAFLUPROST	4	11
NETARSUDIL	4	7
BETAXOLOL	4	3
LATANOPROSTENE BUNOD	4	3
MEMANTINE	4	2
MITOMYCIN	4	2
PILOCARPINE	4	2
CAFFEINE	4	1
FLUOROURACIL	4	1
OMIDENEPAG ISOPROPYL	4	1
PREDNISOLONE ACETATE	4	1
RETINOL	4	1
SEMAGLUTIDE	4	1
TOBRAMYCIN	4	1
ANECORTAVE ACETATE	3	5
CITICOLINE	3	2
RIPASUDIL	3	2
BIMATOPROST GRENOD	3	1
EPIGALOCATECHIN GALLATE	3	1
SEPETAPROST	3	1
VEROSUDIL	2	4
DE-104	2	2
AL-12182	2	1