Diabetic retinopathy

Summary

Diabetic retinopathy (MONDO:0005266) is a disease with 55 cohort genes (195 GWAS associations across 24 studies) and 553 clinical trials. Top therapeutic interventions include bevacizumab, brimonidine, and fenofibrate.

At a glance

• Cohort genes: 55
• GWAS associations: 195
• ClinVar variants: 101
• Clinical trials: 553

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetic retinopathy
Mondo ID	MONDO:0005266
EFO	EFO:0003770
MeSH	D003930
DOID	DOID:8947
ICD-11	1006882070
NCIT	C34538
SNOMED CT	4855003
UMLS	C0011884
MedGen	3786
Is cancer (heuristic)	no

Data availability: 101 ClinVar variants · 195 GWAS associations (24 studies) · 37 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal vascular disorder › diabetic retinopathy

Related subtypes (11): retinal microaneurysm, retinal vascular occlusion, retinal hemangioblastoma, retinal telangiectasia, retinal vasculitis, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, familial retinal arterial macroaneurysm, vasoproliferative tumor of retina, exudative vitreoretinopathy, arteriosclerotic retinopathy, perifoveal exudative vascular anomalous complex

Subtypes (3): proliferative diabetic retinopathy, background diabetic retinopathy, diabetic macular edema

Genetics & variants

GWAS landscape

195 GWAS associations across 24 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7903146	3e-271	TCF7L2	C	0.28
rs34872471	3e-261	TCF7L2	T	0.3
rs1421085	8e-74	FTO	T	0.14
rs7630554	2e-45	IGF2BP2	A	0.12
rs10811661	4e-44	CDKN2B-AS1	T	0.15
chr6:32681483	3e-43		T	0.18
rs9274619	4e-39	HLA-DQB1	A	0.73
chr3:185513392	5e-38		A	0.11
rs1801214	7e-35	WFS1	C	0.1
chr10:94470515	2e-34		T	0.1
chr6:20675792	5e-34		C	0.11
rs2237897	1e-32	KCNQ1	C	0.19
rs4933736	2e-32	Y_RNA - EXOC6	C	0.1
rs9274830	2e-29	HLA-DQB1 - MTCO3P1	C	0.14
rs234864	3e-27	KCNQ1	G	0.09
rs9348441	3e-26	CDKAL1	T	0.09
rs13266634	7e-26	SLC30A8	C	0.1
chr2:43751480	1e-25		T	0.14
rs459193	7e-25	C5orf67	A	0.09
rs9457	2e-24	WFS1	G	0.08
chr2:227157209	3e-24		A	0.09
rs1635852	7e-24	JAZF1	T	0.08
rs738408	3e-22	PNPLA3	C	0.09
rs2972156	5e-22	NYAP2 - MIR5702	C	0.09
rs3747207	7e-22	PNPLA3	G	0.09
rs10195252	2e-21	COBLL1	T	0.08
rs111812200	2e-21	THADA	T	0.12
rs11466334	6e-21	TGFB1	G	0.27
rs10184004	9e-21	GRB14 - COBLL1	C	0.07
chr10:80942620	1e-20		C	0.08

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475689	Verma A	2024	29,668	402,541	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475688	Verma A	2024	11,781	103,431	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479891	Verma A	2024	11,781	103,431	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475687	Verma A	2024	5,658	51,648	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST012174	Imamura M	2021	5,532	5,565	Genome-Wide Association Studies Identify Two Novel Loci Conferring Susceptibility to Diabetic Retinopathy in Japanese Patients with Type 2 Diabetes.
GCST90651220	Liu TY	2025	1,871	219,284	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90079903	Backman JD	2021	1,748	386,182	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083889	Backman JD	2021	1,748	386,182	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90134546	Xue Z	2022	1,652	60,577	Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank.
GCST90435714	Zhou W	2018	1,339	396,859	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	45

MAF distribution

Bucket	Variants
common (>=0.05)	47
low_freq (0.01-0.05)	3
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	21
unknown	15
intergenic_variant	7
missense_variant	3
3_prime_UTR_variant	1
synonymous_variant	1
regulatory_region_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7903146	10	112998590	C>G,T	0.288	intron_variant	TCF7L2	3e-271	Tier 4: intronic/intergenic
rs34872471	10	112994312	T>C	0.292	intron_variant	TCF7L2	3e-261	Tier 4: intronic/intergenic
rs1421085	16	53767042	T>C	0.407	intron_variant	FTO	8e-74	Tier 4: intronic/intergenic
rs7630554	3	185808274	A>G	0.396	intron_variant	IGF2BP2	2e-45	Tier 4: intronic/intergenic
rs10811661	9	22134095	T>A,C	0.175	intergenic_variant	CDKN2B-AS1	4e-44	Tier 4: intronic/intergenic
chr6:32681483				0.105			3e-43	Tier 4: intronic/intergenic
rs9274619	6	32668177	G>A	0.05	intergenic_variant	HLA-DQB1	4e-39	Tier 4: intronic/intergenic
chr3:185513392				0.315			5e-38	Tier 4: intronic/intergenic
rs1801214	4	6301295	C>A,G,T	0.397	missense_variant	WFS1	7e-35	Tier 1: coding
chr10:94470515				0.37			2e-34	Tier 4: intronic/intergenic
chr6:20675792				0.264			5e-34	Tier 4: intronic/intergenic
rs2237897	11	2837316	C>T	0.071	intron_variant	KCNQ1	1e-32	Tier 4: intronic/intergenic
rs4933736	10	92711838	C>T	0.338	intergenic_variant	Y_RNA - EXOC6	2e-32	Tier 4: intronic/intergenic
rs9274830	6	32672059	C>A	0.105	intergenic_variant	HLA-DQB1 - MTCO3P1	2e-29	Tier 4: intronic/intergenic
rs234864	11	2836067	G>A	0.46	intron_variant	KCNQ1	3e-27	Tier 4: intronic/intergenic
rs9348441	6	20680447	T>A	0.25	intron_variant	CDKAL1	3e-26	Tier 4: intronic/intergenic
rs13266634	8	117172544	C>A,T	0.261	missense_variant	SLC30A8	7e-26	Tier 1: coding
chr2:43751480				0.119			1e-25	Tier 4: intronic/intergenic
rs459193	5	56510924	A>C,G,T	0.29	intron_variant	C5orf67	7e-25	Tier 4: intronic/intergenic
rs9457	4	6303072	G>C	0.442	3_prime_UTR_variant	WFS1	2e-24	Tier 2: splice/UTR
chr2:227157209				0.366			3e-24	Tier 4: intronic/intergenic
rs1635852	7	28149792	T>A,C	0.498	intron_variant	JAZF1	7e-24	Tier 4: intronic/intergenic
rs738408	22	43928850	C>A,G,T	0.225	synonymous_variant	PNPLA3	3e-22	Tier 4: intronic/intergenic
rs2972156	2	226253062	C>A,G,T	0.32	intergenic_variant	NYAP2 - MIR5702	5e-22	Tier 4: intronic/intergenic
rs3747207	22	43928975	G>A,C,T	0.219	intron_variant	PNPLA3	7e-22	Tier 4: intronic/intergenic
rs10195252	2	164656581	T>C	0.405	intergenic_variant	COBLL1	2e-21	Tier 4: intronic/intergenic
rs111812200	2	43447139	T>C	0.109	intron_variant	THADA	2e-21	Tier 4: intronic/intergenic
rs11466334	19	41341832	G>A	0.056	intron_variant	TGFB1	6e-21	Tier 4: intronic/intergenic
rs10184004	2	164651879	C>T	0.442	intergenic_variant	GRB14 - COBLL1	9e-21	Tier 4: intronic/intergenic
chr10:80942620				0.451			1e-20	Tier 4: intronic/intergenic

ClinVar germline variants

101 retrieved; paginated sample, class counts are floors:

36 conflicting classifications of pathogenicity, 27 uncertain significance/uncertain risk allele, 25 likely benign, 8 benign/likely benign, 5 uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
3220877	NM_003242.6(TGFBR2):c.-195G>C	LOC129936399	Uncertain risk allele	criteria provided, single submitter
344652	NM_003242.6(TGFBR2):c.-193G>A	LOC129936399	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1001410	NM_003242.6(TGFBR2):c.-337T>A	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1043804	NM_003242.6(TGFBR2):c.283A>G (p.Ile95Val)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1315157	NM_003242.6(TGFBR2):c.94+16260C>A	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1442459	NM_003242.6(TGFBR2):c.371A>T (p.Lys124Met)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
177828	NM_003242.6(TGFBR2):c.-8G>A	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
213914	NM_003242.6(TGFBR2):c.296C>T (p.Thr99Ile)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
3075181	NM_003242.6(TGFBR2):c.310C>A (p.Pro104Thr)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
3220874	NM_003242.6(TGFBR2):c.-26G>T	TGFBR2	Uncertain risk allele	criteria provided, single submitter
3220875	NM_001024847.2(TGFBR2):c.-344C>T	TGFBR2	Uncertain risk allele	criteria provided, single submitter
3220878	NM_003242.6(TGFBR2):c.325C>A (p.His109Asn)	TGFBR2	Uncertain risk allele	criteria provided, single submitter
344650	NM_003242.6(TGFBR2):c.-249T>G	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
344651	NM_003242.6(TGFBR2):c.-228C>A	TGFBR2	Uncertain risk allele	criteria provided, single submitter
452265	NM_003242.6(TGFBR2):c.326A>T (p.His109Leu)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
489351	NM_003242.6(TGFBR2):c.-27G>C	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
543895	NM_003242.6(TGFBR2):c.394A>G (p.Thr132Ala)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
567975	NM_003242.6(TGFBR2):c.175T>C (p.Ser59Pro)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
629218	NM_003242.6(TGFBR2):c.272A>C (p.Asn91Thr)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
629715	NM_003242.6(TGFBR2):c.43G>T (p.Val15Phe)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
835852	NM_003242.6(TGFBR2):c.148C>G (p.Leu50Val)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
858705	NM_003242.6(TGFBR2):c.76C>T (p.Pro26Ser)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
920717	NM_003242.6(TGFBR2):c.58A>G (p.Ile20Val)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
920747	NM_003242.6(TGFBR2):c.1A>G (p.Met1Val)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
921794	NM_003242.6(TGFBR2):c.56G>A (p.Arg19His)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
922243	NM_003242.6(TGFBR2):c.8G>A (p.Arg3Gln)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
922450	NM_003242.6(TGFBR2):c.188A>G (p.Asn63Ser)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
924010	NM_003242.6(TGFBR2):c.352T>C (p.Ser118Pro)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
924974	NM_003242.6(TGFBR2):c.64A>T (p.Ser22Cys)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
927079	NM_003242.6(TGFBR2):c.340G>C (p.Glu114Gln)	TGFBR2	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 30 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCF4	Orphanet:171	Primary sclerosing cholangitis
TCF4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
TCF4	Orphanet:2896	Pitt-Hopkins syndrome
TCF4	Orphanet:98974	Fuchs endothelial corneal dystrophy
TGFBR2	Orphanet:144	Lynch syndrome
TGFBR2	Orphanet:284973	Marfan syndrome type 2
TGFBR2	Orphanet:60030	Loeys-Dietz syndrome
TGFBR2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR2	Orphanet:99977	Squamous cell carcinoma of the esophagus
TNFSF4	Orphanet:2073	Narcolepsy type 1
TNFSF4	Orphanet:536	Systemic lupus erythematosus
ZBTB18	Orphanet:36367	Distal deletion 1q syndrome
TAB2	Orphanet:664401	Cardiac anomalies-short stature-joint hypermobility-facial dysmorphism syndrome due to TAB2 mutation
TAB2	Orphanet:664404	6q25.1 microdeletion syndrome
TNFRSF13B	Orphanet:696907	Common variable immunodeficiency phenotype due to homozygous TACI deficiency
TSEN54	Orphanet:166063	Pontocerebellar hypoplasia type 4
TSEN54	Orphanet:2524	Pontocerebellar hypoplasia type 2
TMEM94	Orphanet:562569	TMEM94-associated congenital heart defect-facial dysmorphism-developmental delay syndrome
MYSM1	Orphanet:508542	Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome
STT3B	Orphanet:370924	STT3B-CDG
AKT3	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
AKT3	Orphanet:99802	Hemimegalencephaly
IRF8	Orphanet:319600	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
INSR	Orphanet:2297	Insulin-resistance syndrome type A
INSR	Orphanet:263458	Hyperinsulinism due to INSR deficiency
INSR	Orphanet:508	Donohue syndrome
INSR	Orphanet:769	Rabson-Mendenhall syndrome
MTHFS	Orphanet:597874	MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome
MYT1L	Orphanet:647799	MYT1L-related developmental delay-intellectual disability-obesity syndrome
MYT1L	Orphanet:699850	2p25.3 microduplication syndrome

Cohort genes → proteins

55 cohort genes, 51 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	54
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX18	HGNC:11595	ENSG00000112837	O95935	T-box transcription factor TBX18	gwas
TCF4	HGNC:11634	ENSG00000196628	P15884	Transcription factor 4	gwas
TGFBR2	HGNC:11773	ENSG00000163513	P37173	TGF-beta receptor type-2	clinvar
TNFSF4	HGNC:11934	ENSG00000117586	P23510	Tumor necrosis factor ligand superfamily member 4	gwas
UCHL3	HGNC:12515	ENSG00000118939	P15374	Ubiquitin carboxyl-terminal hydrolase isozyme L3	gwas
ZBTB18	HGNC:13030	ENSG00000179456	Q99592	Zinc finger and BTB domain-containing protein 18	gwas
MRPS15	HGNC:14504	ENSG00000116898	P82914	Small ribosomal subunit protein uS15m	gwas
PALM2	HGNC:15845			paralemmin 2	gwas
OSBPL10	HGNC:16395	ENSG00000144645	Q9BXB5	Oxysterol-binding protein-related protein 10	gwas
SLC28A3	HGNC:16484	ENSG00000197506	Q9HAS3	Solute carrier family 28 member 3	gwas
CREB5	HGNC:16844	ENSG00000146592	Q02930	Cyclic AMP-responsive element-binding protein 5	gwas
TAB2	HGNC:17075	ENSG00000055208	Q9NYJ8	TGF-beta-activated kinase 1 and MAP3K7-binding protein 2	gwas
TNFRSF13B	HGNC:18153	ENSG00000240505	O14836	Tumor necrosis factor receptor superfamily member 13B	gwas
CASKIN2	HGNC:18200	ENSG00000177303	Q8WXE0	Caskin-2	gwas
RBFOX1	HGNC:18222	ENSG00000078328	Q9NWB1	RNA binding protein fox-1 homolog 1	gwas
HS6ST3	HGNC:19134	ENSG00000185352	Q8IZP7	Heparan-sulfate 6-O-sulfotransferase 3	gwas
TBC1D4	HGNC:19165	ENSG00000136111	O60343	TBC1 domain family member 4	gwas
CMTM8	HGNC:19179	ENSG00000170293	Q8IZV2	CKLF-like MARVEL transmembrane domain-containing protein 8	gwas
CCNL1	HGNC:20569	ENSG00000163660	Q9UK58	Cyclin-L1	gwas
PLXDC2	HGNC:21013	ENSG00000120594	Q6UX71	Plexin domain-containing protein 2	gwas
CEP162	HGNC:21107	ENSG00000135315	Q5TB80	Centrosomal protein of 162 kDa	gwas
CNOT10	HGNC:23817	ENSG00000182973	Q9H9A5	CCR4-NOT transcription complex subunit 10	gwas
COMMD6	HGNC:24015	ENSG00000188243	Q7Z4G1	COMM domain-containing protein 6	gwas
CCDC68	HGNC:24350	ENSG00000166510	Q9H2F9	Coiled-coil domain-containing protein 68	gwas
GRAMD2B	HGNC:24911	ENSG00000155324	Q96HH9	GRAM domain-containing protein 2B	gwas
VEPH1	HGNC:25735	ENSG00000197415	Q14D04	Ventricular zone-expressed PH domain-containing protein homolog 1	gwas
KLHDC7A	HGNC:26791	ENSG00000179023	Q5VTJ3	Kelch domain-containing protein 7A	gwas
UBXN2A	HGNC:27265	ENSG00000173960	P68543	UBX domain-containing protein 2A	gwas
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	gwas
GADL1	HGNC:27949	ENSG00000144644	Q6ZQY3	Acidic amino acid decarboxylase GADL1	gwas
IGSF21	HGNC:28246	ENSG00000117154	Q96ID5	Immunoglobulin superfamily member 21	gwas
TMEM94	HGNC:28983	ENSG00000177728	Q12767	Transmembrane protein 94	gwas
MYSM1	HGNC:29401	ENSG00000162601	Q5VVJ2	Deubiquitinase MYSM1	gwas
MAP3K21	HGNC:29798	ENSG00000143674	Q5TCX8	Mitogen-activated protein kinase kinase kinase 21	gwas
TENM2	HGNC:29943	ENSG00000145934	Q9NT68	Teneurin-2	gwas
OSCP1	HGNC:29971	ENSG00000116885	Q8WVF1	Protein OSCP1	gwas
ARHGAP22	HGNC:30320	ENSG00000128805	Q7Z5H3	Rho GTPase-activating protein 22	gwas
MPRIP	HGNC:30321	ENSG00000133030	Q6WCQ1	Myosin phosphatase Rho-interacting protein	gwas
STT3B	HGNC:30611	ENSG00000163527	Q8TCJ2	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3B	gwas
KRT18P34	HGNC:33403	ENSG00000244515		keratin 18 pseudogene 34	gwas
ST20	HGNC:33520	ENSG00000180953	Q9HBF5	Suppressor of tumorigenicity 20 protein	gwas
VSTM2B	HGNC:33595	ENSG00000187135	A6NLU5	V-set and transmembrane domain-containing protein 2B	gwas
LEKR1	HGNC:33765	ENSG00000197980	Q6ZMV7	Protein LEKR1	gwas
ZNF860	HGNC:34513	ENSG00000197385	A6NHJ4	Zinc finger protein 860	gwas
AKT3	HGNC:393	ENSG00000117020	Q9Y243	RAC-gamma serine/threonine-protein kinase	gwas
GUCY1B1	HGNC:4687	ENSG00000061918	Q02153	Guanylate cyclase soluble subunit beta-1	gwas
LINC01539	HGNC:51307	ENSG00000267712		long intergenic non-protein coding RNA 1539	gwas
LINC01611	HGNC:51791	ENSG00000231776		long intergenic non-protein coding RNA 1611	gwas
IRF8	HGNC:5358	ENSG00000140968	Q02556	Interferon regulatory factor 8	gwas
INSR	HGNC:6091	ENSG00000171105	P06213	Insulin receptor	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX18	T-box transcription factor TBX18	Acts as a transcriptional repressor involved in developmental processes of a variety of tissues and organs, including the heart and coronary vessels, the ureter and the vertebral column.
TCF4	Transcription factor 4	Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif.
TGFBR2	TGF-beta receptor type-2	Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
TNFSF4	Tumor necrosis factor ligand superfamily member 4	Cytokine that binds to TNFRSF4.
UCHL3	Ubiquitin carboxyl-terminal hydrolase isozyme L3	Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins.
ZBTB18	Zinc finger and BTB domain-containing protein 18	Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development.
OSBPL10	Oxysterol-binding protein-related protein 10	Probable lipid transporter involved in lipid countertransport between the endoplasmic reticulum and the plasma membrane.
SLC28A3	Solute carrier family 28 member 3	Sodium-dependent, pyrimidine- and purine-selective.
CREB5	Cyclic AMP-responsive element-binding protein 5	Binds to the cAMP response element and activates transcription.
TAB2	TGF-beta-activated kinase 1 and MAP3K7-binding protein 2	Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of ‘Lys-63’-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF).
TNFRSF13B	Tumor necrosis factor receptor superfamily member 13B	Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity.
RBFOX1	RNA binding protein fox-1 homolog 1	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.
HS6ST3	Heparan-sulfate 6-O-sulfotransferase 3	6-O-sulfation enzyme which catalyzes the transfer of sulfate from 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to position 6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate.
TBC1D4	TBC1 domain family member 4	May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14.
CCNL1	Cyclin-L1	Regulatory component of the cyclin-L-CDK11 complex that regulates transcription and pre-mRNA splicing.
PLXDC2	Plexin domain-containing protein 2	May play a role in tumor angiogenesis.
CEP162	Centrosomal protein of 162 kDa	Required to promote assembly of the transition zone in primary cilia.
CNOT10	CCR4-NOT transcription complex subunit 10	Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational in…
COMMD6	COMM domain-containing protein 6	Scaffold protein in the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex.
CCDC68	Coiled-coil domain-containing protein 68	Centriolar protein required for centriole subdistal appendage assembly and microtubule anchoring in interphase cells.
VEPH1	Ventricular zone-expressed PH domain-containing protein homolog 1	Interacts with TGF-beta receptor type-1 (TGFBR1) and inhibits dissociation of activated SMAD2 from TGFBR1, impeding its nuclear accumulation and resulting in impaired TGF-beta signaling.
UBXN2A	UBX domain-containing protein 2A	Acts to repress the ubiquitination and subsequent endoplasmic reticulum-associated degradation of CHRNA3 by the STUB1-VCP-UBXN2A complex in cortical neurons.
TSEN54	tRNA-splicing endonuclease subunit Sen54	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
GADL1	Acidic amino acid decarboxylase GADL1	May catalyze the decarboxylation of L-aspartate, 3-sulfino-L-alanine (cysteine sulfinic acid), and L-cysteate to beta-alanine, hypotaurine and taurine, respectively.
IGSF21	Immunoglobulin superfamily member 21	Involved in synaptic inhibition in the brain.
TMEM94	Transmembrane protein 94	Could function in the uptake of Mg(2+) from the cytosol into the endoplasmic reticulum and regulate intracellular Mg(2+) homeostasis.
MYSM1	Deubiquitinase MYSM1	Metalloprotease with deubiquitinase activity that plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response.
MAP3K21	Mitogen-activated protein kinase kinase kinase 21	Negative regulator of TLR4 signaling.
TENM2	Teneurin-2	Involved in neural development, regulating the establishment of proper connectivity within the nervous system.
OSCP1	Protein OSCP1	May be involved in drug clearance in the placenta.
ARHGAP22	Rho GTPase-activating protein 22	Rho GTPase-activating protein involved in the signal transduction pathway that regulates endothelial cell capillary tube formation during angiogenesis.
MPRIP	Myosin phosphatase Rho-interacting protein	Targets myosin phosphatase to the actin cytoskeleton.
STT3B	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3B	Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within a…
ST20	Suppressor of tumorigenicity 20 protein	May act as a tumor suppressor.
ZNF860	Zinc finger protein 860	May be involved in transcriptional regulation.
AKT3	RAC-gamma serine/threonine-protein kinase	AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
GUCY1B1	Guanylate cyclase soluble subunit beta-1	Mediates responses to nitric oxide (NO) by catalyzing the biosynthesis of the signaling molecule cGMP.
IRF8	Interferon regulatory factor 8	Transcription factor that specifically binds to the upstream regulatory region of type I interferon (IFN) and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)).
INSR	Insulin receptor	Receptor tyrosine kinase which mediates the pleiotropic actions of insulin.
KCNK1	Potassium channel subfamily K member 1	Ion channel that contributes to passive transmembrane potassium transport and to the regulation of the resting membrane potential in brain astrocytes, but also in kidney and in other tissues.
LLGL2	LLGL scribble cell polarity complex component 2	Part of a complex with GPSM2/LGN, PRKCI/aPKC and PARD6B/Par-6, which may ensure the correct organization and orientation of bipolar spindles for normal cell division.
MTHFS	5-formyltetrahydrofolate cyclo-ligase	Contributes to tetrahydrofolate metabolism.
MYT1L	Myelin transcription factor 1-like protein	Transcription factor that plays a key role in neuronal differentiation by specifically repressing expression of non-neuronal genes during neuron differentiation.
NOX4	NADPH oxidase 4	NADPH oxidase that catalyzes predominantly the reduction of oxygen to H2O2.

Protein-family classification

Druggable: 13 · Difficult: 13 · Unknown: 29 · Druggable fraction: 0.24

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
Kinase	4	2.0×	0.545
Scaffold/PPI	6	1.9×	0.545
Ion channel	1	2.0×	0.726
Protease	2	1.3×	0.726
Antibody/Immunoglobulin	2	1.1×	0.726
Transcription factor	7	1.1×	0.726
Other/Unknown	29	0.9×	0.726
Enzyme (other)	4	0.9×	0.726

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX18	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TCF4	Transcription factor	no	7.6.2.3	bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
TGFBR2	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
TNFSF4	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_CS
UCHL3	Protease	yes	3.4.19.12	Peptidase_C12_UCH, Peptidase_C12_UCH_sf, Papain-like_cys_pep_sf
ZBTB18	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
MRPS15	Other/Unknown	no		Ribosomal_uS15, Ribosomal_uS15_bact, uS15_NS1_RNA-bd_sf
PALM2	Other/Unknown	no
OSBPL10	Scaffold/PPI	no		Oxysterol-bd, PH_domain, PH-like_dom_sf
SLC28A3	Other/Unknown	no		CNT_N_dom, C_nuclsd_transpt, Gate_dom
CREB5	Transcription factor	no		bZIP, Znf_C2H2_type, TF_CRE-BP1-typ
TAB2	Transcription factor	no		Znf_RanBP2, CUE, Znf_RanBP2_sf
TNFRSF13B	Other/Unknown	no		TACI_Cys-rich-dom, TNFR_13B
CASKIN2	Scaffold/PPI	no		SH3_domain, SAM, Ankyrin_rpt
RBFOX1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
HS6ST3	Other/Unknown	no		Sulfotransferase, Heparan_SO4-6-sulfoTrfase, P-loop_NTPase
TBC1D4	Other/Unknown	no		Rab-GAP-TBC_dom, PTB/PI_dom, PH-like_dom_sf
CMTM8	Other/Unknown	no		Marvel, MAL, MARVEL-CKLF_proteins
CCNL1	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
PLXDC2	Other/Unknown	no		Plexin_repeat, PSI, PLXDC
CEP162	Other/Unknown	no		CEP162-like
CNOT10	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, CNOT10
COMMD6	Other/Unknown	no		COMM, COMMD4/6/7/8
CCDC68	Other/Unknown	no		Tuftelin_GRINL1A/MYZAP/CCD68
GRAMD2B	Other/Unknown	no		GRAM, PH-like_dom_sf, GRAM_domain_protein_2B
VEPH1	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, ARM-type_fold
KLHDC7A	Other/Unknown	no		Kelch_1, Kelch-typ_b-propeller, Kelch/BTB_domain_protein
UBXN2A	Other/Unknown	no		UBX_dom, SEP_domain, Ubiquitin-like_domsf
TSEN54	Enzyme (other)	yes	4.6.1.16	tRNA_splic_suSen54_N, tRNA_splic_suSen54
GADL1	Other/Unknown	no		PyrdxlP-dep_de-COase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
IGSF21	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
TMEM94	Other/Unknown	no		ATPase_P-typ_TM_dom_sf, TMEM94
MYSM1	Protease	yes		JAMM/MPN+_dom, SANT/Myb, SWIRM
MAP3K21	Kinase	yes	2.7.11.25	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, SH3_domain
TENM2	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, YD
OSCP1	Other/Unknown	no		OSCP1
ARHGAP22	Scaffold/PPI	no		RhoGAP_dom, PH_domain, Rho_GTPase_activation_prot
MPRIP	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, M-RIP_PH
STT3B	Enzyme (other)	yes	2.4.99.18	Oligo_trans_STT3, STT3_N, STT3-PglB_core
KRT18P34	Other/Unknown	no
ST20	Other/Unknown	no
VSTM2B	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
LEKR1	Other/Unknown	no		LEKR1
ZNF860	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
AKT3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
GUCY1B1	Enzyme (other)	yes	4.6.1.2	A/G_cyclase, Heme_NO-bd, HNOB_dom_associated
LINC01539	Other/Unknown	no
LINC01611	Other/Unknown	no
IRF8	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
INSR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 1.

52 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)	54
unknown	1

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	7
male germ line stem cell (sensu Vertebrata) in testis	7
cortical plate	5
secondary oocyte	4
middle temporal gyrus	4
right lobe of liver	4
buccal mucosa cell	4
primordial germ cell in gonad	3
right testis	3
ventricular zone	3
left testis	3
cerebellar hemisphere	3
right uterine tube	3
cardiac muscle of right atrium	3
popliteal artery	2
tibial artery	2
endothelial cell	2
pericardium	2
monocyte	2
mononuclear cell	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX18	162	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
TCF4	292	ubiquitous	marker	endothelial cell, skin of hip, pericardium
TGFBR2	289	ubiquitous	marker	pericardium, tibia, parietal pleura
TNFSF4	181	broad	marker	primordial germ cell in gonad, monocyte, mononuclear cell
UCHL3	152	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
ZBTB18	292	ubiquitous	marker	cerebellar vermis, paraflocculus, cortical plate
MRPS15	283	ubiquitous	marker	biceps brachii, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii
PALM2
OSBPL10	264	ubiquitous	marker	secondary oocyte, oocyte, right testis
SLC28A3	174	broad	marker	cartilage tissue, secondary oocyte, germinal epithelium of ovary
CREB5	252	ubiquitous	marker	synovial joint, ventricular zone, blood
TAB2	293	ubiquitous	marker	parotid gland, ventricular zone, colonic epithelium
TNFRSF13B	158	tissue_specific	marker	type B pancreatic cell, olfactory bulb, spleen
CASKIN2	253	ubiquitous	marker	olfactory bulb, sural nerve, tibial nerve
RBFOX1	220	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cortical plate
HS6ST3	183	broad	marker	lateral nuclear group of thalamus, middle temporal gyrus, parietal lobe
TBC1D4	290	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, renal medulla, diaphragm
CMTM8	204	ubiquitous	marker	secondary oocyte, body of pancreas, right lobe of liver
CCNL1	293	ubiquitous	marker	mucosa of stomach, granulocyte, left uterine tube
PLXDC2	279	ubiquitous	marker	calcaneal tendon, tendon of biceps brachii, tendon
CEP162	245	ubiquitous	marker	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, sperm
CNOT10	204	ubiquitous	marker	right testis, left testis, male germ line stem cell (sensu Vertebrata) in testis
COMMD6	255	ubiquitous	marker	upper arm skin, ganglionic eminence, left ovary
CCDC68	202	broad	marker	rectum, jejunal mucosa, right lung
GRAMD2B	282	ubiquitous	marker	calcaneal tendon, medial globus pallidus, globus pallidus
VEPH1	178	ubiquitous	marker	pigmented layer of retina, ventricular zone, kidney epithelium
KLHDC7A	99	tissue_specific	marker	secondary oocyte, oocyte, adult mammalian kidney
UBXN2A	261	ubiquitous	marker	buccal mucosa cell, pancreatic ductal cell, renal medulla
TSEN54	232	ubiquitous	marker	granulocyte, right uterine tube, cerebellar hemisphere
GADL1	79	tissue_specific	marker	buccal mucosa cell, germinal epithelium of ovary, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYSM1	6,171
TGFBR2	5,777
MRPS15	4,773
INSR	4,446
IRF8	3,554
AKT3	3,392
TCF4	3,342
RBFOX1	2,990
STT3B	2,615
TAB2	2,606

Intra-cohort edges

A	B	Sources
AKT3	ZBTB18	string_interaction
ARHGAP22	PLXDC2	string_interaction
CASKIN2	TMEM94	string_interaction
CCNL1	LEKR1	string_interaction
COMMD6	UCHL3	string_interaction
GADL1	OSBPL10	string_interaction
IGSF21	KLHDC7A	string_interaction
INSR	STT3B	intact
MRPS15	OSCP1	string_interaction
OSBPL10	STT3B	string_interaction
OSBPL10	ZNF860	string_interaction

Structural data

PDB: 26 · AlphaFold-only: 25 · No structure: 4

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INSR	P06213	88
MRPS15	P82914	77
TGFBR2	P37173	22
GUCY1B1	Q02153	14
LLGL2	Q6P1M3	10
TAB2	Q9NYJ8	6
TMEM94	Q12767	6
TCF4	P15884	5
UCHL3	P15374	5
TSEN54	Q7Z6J9	5
CASKIN2	Q8WXE0	4
RBFOX1	Q9NWB1	4
MTHFS	P49914	4
COMMD6	Q7Z4G1	3
TNFRSF13B	O14836	2
TBC1D4	O60343	2
CNOT10	Q9H9A5	2
MYSM1	Q5VVJ2	2
TENM2	Q9NT68	2
AKT3	Q9Y243	2
TNFSF4	P23510	1
ZBTB18	Q99592	1
SLC28A3	Q9HAS3	1
MAP3K21	Q5TCX8	1
STT3B	Q8TCJ2	1
KCNK1	O00180	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GADL1	Q6ZQY3	94.77
LEKR1	Q6ZMV7	92.75
NOX4	Q9NPH5	86.98
HS6ST3	Q8IZP7	81.20
CCDC68	Q9H2F9	81.20
OSCP1	Q8WVF1	77.95
CMTM8	Q8IZV2	77.37
IGSF21	Q96ID5	76.60
IRF8	Q02556	75.54
OSBPL10	Q9BXB5	75.03
UBXN2A	P68543	73.68
VEPH1	Q14D04	73.24
ARHGAP22	Q7Z5H3	70.00
PLXDC2	Q6UX71	69.80
CCNL1	Q9UK58	68.90
VSTM2B	A6NLU5	68.84
MPRIP	Q6WCQ1	65.71
GRAMD2B	Q96HH9	63.97
CEP162	Q5TB80	63.93
ZNF860	A6NHJ4	63.66
KLHDC7A	Q5VTJ3	61.91
TBX18	O95935	61.09
ST20	Q9HBF5	59.57
CREB5	Q02930	57.95
MYT1L	Q9UL68	55.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 219. Enrichment computed across 55 evidence-associated genes (29 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 29 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TGFBR2 MSI Frameshift Mutants in Cancer	1	196.9×	0.163	TGFBR2
Tandem of pore domain in a weak inwardly rectifying K+ channels (TWIK)	1	131.3×	0.163	KCNK1
Loss of Function of TGFBR2 in Cancer	1	131.3×	0.163	TGFBR2
TGFBR2 Kinase Domain Mutants in Cancer	1	131.3×	0.163	TGFBR2
AKT-mediated inactivation of FOXO1A	1	98.5×	0.163	AKT3
TGFBR1 LBD Mutants in Cancer	1	98.5×	0.163	TGFBR2
Inhibition of TSC complex formation by AKT (PKB)	1	78.8×	0.163	AKT3
Loss of Function of TGFBR1 in Cancer	1	78.8×	0.163	TGFBR2
IRS activation	1	78.8×	0.163	INSR
MECP2 regulates transcription factors	1	78.8×	0.163	RBFOX1
Loss of Function of SMAD2/3 in Cancer	1	65.6×	0.163	TGFBR2
Signaling by TGF-beta Receptor Complex in Cancer	1	65.6×	0.163	TGFBR2
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	65.6×	0.163	TGFBR2
TGFBR1 KD Mutants in Cancer	1	65.6×	0.163	TGFBR2
G-protein beta:gamma signalling	1	65.6×	0.163	AKT3
RUNX2 regulates genes involved in cell migration	1	49.2×	0.163	AKT3
TGFBR3 regulates TGF-beta signaling	1	49.2×	0.163	TGFBR2
AKT phosphorylates targets in the nucleus	1	39.4×	0.163	AKT3
IRAK2 mediated activation of TAK1 complex	1	39.4×	0.163	TAB2
STAT5 activation downstream of FLT3 ITD mutants	1	39.4×	0.163	NOX4
Signal attenuation	1	35.8×	0.163	INSR
Aspartate and asparagine metabolism	1	35.8×	0.163	GADL1
TICAM1,TRAF6-dependent induction of TAK1 complex	1	35.8×	0.163	TAB2
Alpha-protein kinase 1 signaling pathway	1	35.8×	0.163	TAB2
Ribavirin ADME	1	35.8×	0.163	SLC28A3
Tandem pore domain potassium channels	1	32.8×	0.163	KCNK1
Degradation of cysteine and homocysteine	1	32.8×	0.163	GADL1
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	32.8×	0.163	SLC28A3
Regulation of localization of FOXO transcription factors	1	32.8×	0.163	AKT3
Signaling by Insulin receptor	1	30.3×	0.163	INSR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 44 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of tolerance induction to self antigen	1	383.0×	0.071	TGFBR2
positive regulation of B cell tolerance induction	1	383.0×	0.071	TGFBR2
folic acid-containing compound biosynthetic process	1	383.0×	0.071	MTHFS
pyrimidine nucleoside transport	1	383.0×	0.071	SLC28A3
T-helper 2 cell activation	1	383.0×	0.071	TNFSF4
response to nitrogen dioxide	1	383.0×	0.071	TNFSF4
folic acid catabolic process	1	383.0×	0.071	MTHFS
sinoatrial node cell fate commitment	1	383.0×	0.071	TBX18
magnesium ion transport from cytosol to endoplasmic reticulum	1	383.0×	0.071	TMEM94
positive regulation of CD4-positive, alpha-beta T cell costimulation	1	383.0×	0.071	TNFSF4
inferior endocardial cushion morphogenesis	1	383.0×	0.071	TGFBR2
positive regulation of interleukin-4-dependent isotype switching to IgE isotypes	1	383.0×	0.071	TNFSF4
plasmacytoid dendritic cell differentiation	1	191.5×	0.077	IRF8
formate metabolic process	1	191.5×	0.077	MTHFS
negative regulation of vesicle fusion	1	191.5×	0.077	TBC1D4
memory T cell activation	1	191.5×	0.077	TNFSF4
positive regulation of meiotic cell cycle	1	191.5×	0.077	INSR
bronchus morphogenesis	1	191.5×	0.077	TGFBR2
mammary gland morphogenesis	1	191.5×	0.077	TGFBR2
regulation of female gonad development	1	191.5×	0.077	INSR
tRNA-type intron splice site recognition and cleavage	1	127.7×	0.077	TSEN54
positive regulation of immunoglobulin mediated immune response	1	127.7×	0.077	TNFSF4
establishment or maintenance of polarity of embryonic epithelium	1	127.7×	0.077	LLGL2
neural plate anterior/posterior regionalization	1	127.7×	0.077	TBX18
protein-DNA complex assembly	1	127.7×	0.077	TCF4
retrograde trans-synaptic signaling by trans-synaptic protein complex	1	127.7×	0.077	TENM2
miRNA transport	1	127.7×	0.077	TGFBR2
follicular B cell differentiation	1	95.8×	0.077	IRF8
positive regulation of T cell tolerance induction	1	95.8×	0.077	TGFBR2
purine nucleoside transmembrane transport	1	95.8×	0.077	SLC28A3

Therapeutics

Drugs indicated for this disease

4 approved, 9 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Aflibercept	Approved (phase 4)
Captopril	Approved (phase 4)
Dexamethasone	Approved (phase 4)
Ranibizumab	Approved (phase 4)
Aspirin	Phase 3 (in late-stage trials)
Bevacizumab	Phase 3 (in late-stage trials)
Dapagliflozin	Phase 3 (in late-stage trials)
Fenofibrate	Phase 3 (in late-stage trials)
Pemafibrate	Phase 3 (in late-stage trials)
Ruboxistaurin	Phase 3 (in late-stage trials)
Simvastatin	Phase 3 (in late-stage trials)
Sorbinil	Phase 3 (in late-stage trials)
Triamcinolone Acetonide	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Brimonidine, Darapladib, Sulodexide.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 7 · Phased (≥1): 8 · Undrugged: 47

Druggability breadth: 14 of 55 evidence-associated genes (25%) 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
TGFBR2	PONATINIB
UCHL3	MENADIONE
SLC28A3	ADENOSINE
AKT3	CAPIVASERTIB
GUCY1B1	BENZYDAMINE
INSR	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
INSR	36	4
TGFBR2	22	4
AKT3	18	4
NOX4	5	3
UCHL3	2	4
SLC28A3	2	4
GUCY1B1	2	4
TCF4	1	2
TBX18	0	0
TNFSF4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	INSR, TGFBR2
SORAFENIB	4	INSR, TGFBR2
DABRAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
DASATINIB	4	TGFBR2
MENADIONE	4	UCHL3
ADENOSINE	4	SLC28A3
CAPIVASERTIB	4	AKT3
MIDOSTAURIN	4	AKT3
BENZYDAMINE	4	GUCY1B1
NERATINIB	4	INSR
INFIGRATINIB PHOSPHATE	4	INSR
INFIGRATINIB	4	INSR
ENTRECTINIB	4	INSR
CERITINIB	4	INSR
OSIMERTINIB	4	INSR
BRIGATINIB	4	INSR
NINTEDANIB	4	INSR
SUNITINIB	4	INSR
LAPATINIB	4	INSR
CRIZOTINIB	4	INSR
CANERTINIB	3	TGFBR2
ALVOCIDIB	3	TGFBR2
LESTAURTINIB	3	AKT3, INSR, TGFBR2
PERIFOSINE	3	UCHL3
URIDINE	3	SLC28A3
IPATASERTIB	3	AKT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
INSR	954	Binding:900, Functional:49, ADMET:4, Toxicity:1
AKT3	660	Binding:644, Functional:16
TGFBR2	188	Binding:188
MAP3K21	45	Binding:45
GUCY1B1	45	Binding:40, Functional:5
UCHL3	36	Binding:36
TCF4	31	Binding:31
NOX4	29	Binding:27, Unclassified:1, Functional:1
SLC28A3	3	ADMET:2, Binding:1
STT3B	2	Binding:2
TAB2	1	Binding:1
CNOT10	1	Binding:1
TMEM94	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter
TGFBR2	2.7.10.2	non-specific protein-tyrosine kinase
UCHL3	3.4.19.12	ubiquitinyl hydrolase 1
TSEN54	4.6.1.16	tRNA-intron lyase
MAP3K21	2.7.11.25	mitogen-activated protein kinase kinase kinase
STT3B	2.4.99.18	dolichyl-diphosphooligosaccharide-protein glycotransferase
AKT3	2.7.11.1	non-specific serine/threonine protein kinase
GUCY1B1	4.6.1.2	guanylate cyclase
INSR	2.7.10.1	receptor protein-tyrosine kinase
MTHFS	6.3.3.2	5-formyltetrahydrofolate cyclo-ligase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TGFBR2	188
AKT3	660
INSR	954

Pharmacogenomics

Cohort genes with a PharmGKB record: 52; 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)
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	INSR, TGFBR2
SORAFENIB	4	INSR, TGFBR2
DABRAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
DASATINIB	4	TGFBR2
MENADIONE	4	UCHL3
ADENOSINE	4	SLC28A3
CAPIVASERTIB	4	AKT3
MIDOSTAURIN	4	AKT3
BENZYDAMINE	4	GUCY1B1
NERATINIB	4	INSR
INFIGRATINIB PHOSPHATE	4	INSR
INFIGRATINIB	4	INSR
ENTRECTINIB	4	INSR
CERITINIB	4	INSR
OSIMERTINIB	4	INSR
BRIGATINIB	4	INSR
NINTEDANIB	4	INSR
SUNITINIB	4	INSR
LAPATINIB	4	INSR
CRIZOTINIB	4	INSR
CANERTINIB	3	TGFBR2
ALVOCIDIB	3	TGFBR2
LESTAURTINIB	3	AKT3, INSR, TGFBR2
PERIFOSINE	3	UCHL3
URIDINE	3	SLC28A3
IPATASERTIB	3	AKT3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	TGFBR2, UCHL3, SLC28A3, AKT3, GUCY1B1, INSR
B	Phased (≥1) drug, not yet approved	2	TCF4, NOX4
C	Druggable family + PDB, no drug	6	TSEN54, MYSM1, MAP3K21, STT3B, KCNK1, MTHFS
D	Druggable family + AlphaFold only, no drug	2	IGSF21, VSTM2B
E	Difficult family or no structure, no drug	39	TBX18, TNFSF4, ZBTB18, MRPS15, PALM2, OSBPL10, CREB5, TAB2, TNFRSF13B, CASKIN2 (+29 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COMMD6	0	UCHL3
TBX18	0	—
TNFSF4	0	—
ZBTB18	0	—
MRPS15	0	—
PALM2	0	—
OSBPL10	0	—
CREB5	0	—
TAB2	1	—
TNFRSF13B	0	—
CASKIN2	0	—
RBFOX1	0	—
HS6ST3	0	—
TBC1D4	0	—
CMTM8	0	—
CCNL1	0	—
PLXDC2	0	—
CEP162	0	—
CNOT10	1	—
CCDC68	0	—
GRAMD2B	0	—
VEPH1	0	—
KLHDC7A	0	—
UBXN2A	0	—
TSEN54	0	—
GADL1	0	—
IGSF21	0	—
TMEM94	1	—
MYSM1	0	—
MAP3K21	45	—

Clinical trials & evidence

Clinical trials

Clinical trials: 553.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	361
PHASE2	60
PHASE3	44
PHASE4	39
PHASE1	24
PHASE1/PHASE2	11
PHASE2/PHASE3	7
EARLY_PHASE1	7

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06191094	PHASE4	ENROLLING_BY_INVITATION	Pre-operative Vabysmo in Patients With Non-clearing Vitreous Hemorrhage Secondary to Proliferative Diabetic Retinopathy
NCT06660940	PHASE4	NOT_YET_RECRUITING	Clinical Trial of Keluoxin Capsules in the Treatment of Diabetic Kidney Disease with Diabetic Retinopathy
NCT07301775	PHASE4	NOT_YET_RECRUITING	Comparing Single Versus Multiple Anti-VEGF Injections in Diabetic Patients Undergoing Cataract Surgery
NCT07456826	PHASE4	ENROLLING_BY_INVITATION	Study Evaluating the Efficacy and Safety of Chloroprocaine HCl Ophthalmic Gel 3% vs Proparacaine Ophthalmic Solution 0.5% Plus Subconjunctival Lidocaine in Patients Undergoing Intravitreal Injections
NCT00411970	PHASE4	COMPLETED	20- Versus 23- Gauge System for Pars Plana Vitrectomy
NCT00496405	PHASE4	WITHDRAWN	Unilateral Bevacizumab for Bilateral Diabetic Macular Edema
NCT00677664	PHASE4	UNKNOWN	Effects of Copaxone in the Retinal Function in Diabetic Patients After Panphotocoagulation
NCT01223612	PHASE4	COMPLETED	Lucentis (Ranibizumab) in Diabetic Macular Oedema: a Treatment Evaluation
NCT01225653	PHASE4	COMPLETED	Topical Application of Latanoprost in Diabetic Retinopathy
NCT01257815	PHASE4	COMPLETED	Ranibizumab Treatment of Diabetic Macular Oedema With Bimonthly Monitoring After a Phase of Initial Treatment
NCT01306981	PHASE4	COMPLETED	Ranibizumab in Diabetic Vitrectomy. A Prospective, Randomised Controlled Trial of Ranibizumab Pre-treatment in Diabetic Vitrectomy - a Pilot Study
NCT01382498	PHASE4	UNKNOWN	Effect of Doxium on High Sensitivity CRP and Endothelin-1 Serum Levels in Patients With Diabetic Retinopathy
NCT01504724	PHASE4	COMPLETED	Effect of the Adjunctive IVB Before PRP
NCT01591902	PHASE4	TERMINATED	Diabetic Retinopathy in HIV Subjects Treated With EGRIFTA®
NCT01824043	PHASE4	UNKNOWN	Use of Intravitreal Ranibizumab in the Treatment of Vitreous Hemorrhage
NCT01927315	PHASE4	COMPLETED	Effects of Fenofibrate on Endothelial Progenitor Cells in Diabetes
NCT02249897	PHASE4	COMPLETED	PRELIMINARY EVALUATION OF PHARMACOLOGICAL LOWERING OF AGEs
NCT02366468	PHASE4	COMPLETED	Study of Efficacy of Ranibizumab in Different Regimens in Patients With Diabetic Macula Edema
NCT02432547	PHASE4	COMPLETED	Laser Therapy Combined With Intravitreal Aflibercept vs Intravitreal Aflibercept Monotherapy (LADAMO)
NCT02559180	PHASE4	COMPLETED	Treatment of Diabetic Macular Edema With Aflibercept in Subjects Previously Treated With Ranibizumab or Bevacizumab
NCT02647515	PHASE4	COMPLETED	Intravitreal Ranibizumab Injection as Adjuvant in the Treatment of Postvitrectomy Diabetic Vitreous Hemorrhage Accompanied by Neovascular Glaucoma
NCT02874313	PHASE4	COMPLETED	CPAP Effect on the Progression of Diabetic Retinopathy in Patients With Sleep Apnea
NCT03439345	PHASE4	COMPLETED	Lowering Events in Non-proliferative Retinopathy in Scotland
NCT03453281	PHASE4	COMPLETED	Early Anatomical, Physiological, and Clinical Changes in Diabetic Macular Edema After Intravitreal Aflibercept Injection
NCT03962296	PHASE4	COMPLETED	A Multicenter, Randomized, Double-blind Non-inferiority Trial to Evaluate the Efficacy and Safety of Entelon®
NCT04018482	PHASE4	COMPLETED	Povidone Iodine vs AVEnova: A Pre-injection Disinfection Study (PAVE Study)
NCT04038125	PHASE4	UNKNOWN	Increase in Capillary Plexus Density Level Following the Use of Ozurdex for the Treatment of DME
NCT04140201	PHASE4	UNKNOWN	Effect of Lipid Lowering Agents on Diabetic Retinopathy and Cardiovascular Risk of Diabetic Patients
NCT04215445	PHASE4	UNKNOWN	Effect of SGLT2 Inhibition on OCT-A Parameters in Diabetic CKD
NCT04283162	PHASE4	UNKNOWN	Using Calcium Dobesilate to Treat Chinese Patients With Mild to Moderate Non-proliferative Diabetic Retinopathy
NCT04359771	PHASE4	COMPLETED	Transfoveal Micropulse Laser for Center Involving Diabetic Macular Edema
NCT04448496	PHASE4	UNKNOWN	Prospective Trial of Dexamethasone implAnt for Treatment Naïve diabeTic Macular Edema
NCT04619303	PHASE4	COMPLETED	Intravitreal Dexamethasone vs Bevacizumab in Aboriginal People With DMO
NCT04674254	PHASE4	COMPLETED	Macular Perfusion Changes After Anti-VEGF Versus Targeted Retinal Photocoagulation in Proliferative Diabetic Retinopathy
NCT04708145	PHASE4	COMPLETED	Long-Term Efficacy and Safety of Intravitreal Aflibercept Injections for the Treatment of Diabetic Retinopathy for Subjects Who Completed the 2-Year PANORAMA Trial
NCT04991350	PHASE4	TERMINATED	Effect of Ranibizumab Versus Bevacizumab on the Macular Perfusion in Diabetic Macular Edema
NCT05386160	PHASE4	UNKNOWN	Phacoemulsification Combined With Intravitreal Injection of Ranibizumab Prevent Postoperative Capillary Non-perfusion Zone Progress in Non-proliferative Diabetic Retinopathy
NCT06708637	PHASE4	COMPLETED	Ocular Safety and Usability Study for FYB203 PFS
NCT07090044	PHASE4	COMPLETED	Comparing Post-intravitreal Injection Pain Scores Using Loteprednol, Bromfenac Sodium, and Artificial Tears Over a 24-hour Period
NCT01320345	PHASE3	ACTIVE_NOT_RECRUITING	The Fenofibrate And Microvascular Events in Type 1 Diabetes Eye.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEVACIZUMAB	4	19
BRIMONIDINE	4	12
FENOFIBRATE	4	6
RANIBIZUMAB	4	6
AFLIBERCEPT	4	5
OCTREOTIDE	4	4
ACETAZOLAMIDE	4	2
DORZOLAMIDE	4	2
FARICIMAB	4	2
FINERENONE	4	2
FLUORESCEIN	4	2
POVIDONE-IODINE	4	2
RUCAPARIB	4	2
TRIAMCINOLONE	4	2
TRIAMCINOLONE ACETONIDE	4	2
BROMFENAC	4	1
CHOLESTYRAMINE	4	1
CLOPIDOGREL BISULFATE	4	1
EMPAGLIFLOZIN	4	1
GINKGO	4	1
HYPOCHLOROUS ACID	4	1
IRBESARTAN	4	1
LATANOPROST	4	1
LISINOPRIL	4	1
LISINOPRIL ANHYDROUS	4	1
LOTEPREDNOL ETABONATE	4	1
MANNITOL	4	1
MECOBALAMIN	4	1
NEPAFENAC	4	1
OCRIPLASMIN	4	1