Wet macular degeneration

Summary

Wet macular degeneration (MONDO:0005417) is a disease with 63 cohort genes (89 GWAS associations across 10 studies) and 119 clinical trials. The dominant Reactome pathway is Regulation of Complement cascade (9 cohort genes). Top therapeutic interventions include aflibercept, ranibizumab, and faricimab.

At a glance

• Cohort genes: 63
• GWAS associations: 89
• Clinical trials: 119

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	wet macular degeneration
Mondo ID	MONDO:0005417
EFO	EFO:0004683
MeSH	D057135
DOID	DOID:10873
SNOMED CT	414173003
UMLS	C2237660
MedGen	389185
GARD	0024181
Is cancer (heuristic)	no

Also known as: exudative senile macular degeneration of retina · wet age related macular degeneration · wet AMD · wet ARMD

Data availability: 89 GWAS associations (10 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › macular degeneration › degeneration of macula and posterior pole › age-related macular degeneration › wet macular degeneration

Related subtypes (14): age related macular degeneration 2, age related macular degeneration 1, macular degeneration, age-related, 3, age related macular degeneration 7, age related macular degeneration 4, age related macular degeneration 9, age related macular degeneration 10, age related macular degeneration 11, age related macular degeneration 6, age related macular degeneration 8, age related macular degeneration 12, age related macular degeneration 14, macular dystrophy with central cone involvement, dry age related macular degeneration

Genetics & variants

GWAS landscape

89 GWAS associations across 10 studies. Top hits map to 31 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs61818925	6e-165	CFHR1 - CFHR4	?	1.67
rs10490924	6e-147	HTRA1-AS1, ARMS2	T	2.52
rs1061170	1e-108	CFH	?	2.78
rs116503776	1e-103	SKIC2	?	1.75
rs2230199	4e-69	C3	?	1.43
rs187328863	1e-68	KCNT2	?	2.27
rs800292	2e-59	CFH	G	1.8
rs429358	2e-42	APOE	?	1.43
rs10737680	8e-38	CFH	?	1.69
rs35292876	8e-37	CFH	?	2.42
rs147859257	3e-28	C3	?	2.86
rs148553336	9e-26	KCNT2 - CFH	?	3.45
CFH	1e-25		?
ARMS2-HTRA1	1e-25		?
rs5754227	1e-24	SYN3	?	1.3
rs121913059	9e-24	CFH	?	20.28
rs2303790	6e-22	CETP	?	1.7
rs5817082	4e-19	CETP	?	1.19
rs17231506	2e-18	HERPUD1 - CETP	?	1.16
rs2295334	6e-18	SCIRT, LINC03040	?	1.28
rs641153	1e-17	CFB	?	2.22
rs10033900	5e-17	CFI	?	1.15
rs11200638	5e-17	HTRA1, HTRA1-AS1	A	2.12
rs201459901	3e-16	LINC01742 - HSPD1P19	?	1.32
rs12019136	2e-15	FUT6	?	1.41
rs2043085	4e-15	ALDH1A2	?	1.15
rs62358361	1e-14	C9	?	1.8
rs943080	1e-14	LINC02537 - LINC01512	?	1.14
rs62247658	2e-14	ADAMTS9-AS2	?	1.14
rs3764261	2e-12	HERPUD1 - CETP	?	1.41

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST003219	Fritsche LG	2015	16,144	17,832	A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
GCST90013852	Han X	2020	8,544	14,590	The effects of eight serum lipid biomarkers on age-related macular degeneration risk: a Mendelian randomization study.
GCST90428459	Fan Q	2023	3,128	5,493	Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes.
GCST002766	Cheng CY	2015	2,119	5,691	New loci and coding variants confer risk for age-related macular degeneration in East Asians.
GCST001577	Sobrin L	2012	1,775	0	Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.
GCST001579	Sobrin L	2012	1,775	4,134	Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.
GCST004737	Ruamviboonsuk P	2017	377	1,074	Genome-wide association study of neovascular age-related macular degeneration in the Thai population.
GCST90481908	Verma A	2024	274	450,375	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90428460	Fan Q	2023	0	0	Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes.
GCST005358	Yan Q	2018	0	0	Genome-wide Analysis of Disease Progression in Age-related Macular Degeneration.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	10
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	38

MAF distribution

Bucket	Variants
common (>=0.05)	38
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	12

Functional consequences

Consequence	Count
intron_variant	21
intergenic_variant	12
missense_variant	10
synonymous_variant	2
unknown	2
non_coding_transcript_exon_variant	1
splice_polypyrimidine_tract_variant	1
splice_donor_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs10922109	1	196735502	C>A,T	0.05	intron_variant	CFH		Tier 4: intronic/intergenic
rs570618	1	196687934	T>C,G	0.05	intron_variant	CFH		Tier 4: intronic/intergenic
rs3750846	10	122456049	T>C	0.05	intron_variant	HTRA1-AS1, ARMS2		Tier 4: intronic/intergenic
rs61818925	1	196846320	T>A,G	0.05	intergenic_variant	CFHR1 - CFHR4	6e-165	Tier 4: intronic/intergenic
rs10490924	10	122454932	G>C,T	0.42	missense_variant	HTRA1-AS1, ARMS2	6e-147	Tier 1: coding
rs1061170	1	196690107	C>A,G,T	0.371	missense_variant	CFH	1e-108	Tier 1: coding
rs116503776	6	31962685			intron_variant	SKIC2	1e-103	Tier 4: intronic/intergenic
rs2230199	19	6718376	G>A,C,T	0.05	missense_variant	C3	4e-69	Tier 1: coding
rs187328863	1	196411028	C>T	0.05	intron_variant	KCNT2	1e-68	Tier 4: intronic/intergenic
rs800292	1	196673103	G>A,C,T	0.41	missense_variant	CFH	2e-59	Tier 1: coding
rs429358	19	44908684	T>C	0.05	missense_variant	APOE	2e-42	Tier 1: coding
rs10737680	1	196710325	A>C,T	0.05	intron_variant	CFH	8e-38	Tier 4: intronic/intergenic
rs35292876	1	196737512	C>A,T		synonymous_variant	CFH	8e-37	Tier 4: intronic/intergenic
rs147859257	19	6718135	T>G		missense_variant	C3	3e-28	Tier 1: coding
rs148553336	1	196644043	T>C		intergenic_variant	KCNT2 - CFH	9e-26	Tier 4: intronic/intergenic
CFH							1e-25	Tier 4: intronic/intergenic
ARMS2-HTRA1							1e-25	Tier 4: intronic/intergenic
rs5754227	22	32709831	T>C	0.05	intron_variant	SYN3	1e-24	Tier 4: intronic/intergenic
rs121913059	1	196747245	C>T		missense_variant	CFH	9e-24	Tier 1: coding
rs2303790	16	56983380	A>G		missense_variant	CETP	6e-22	Tier 1: coding
rs5817082	16	56963438	C>CA	0.05	intron_variant	CETP	4e-19	Tier 4: intronic/intergenic
rs17231506	16	56960616	C>G,T	0.05	intergenic_variant	HERPUD1 - CETP	2e-18	Tier 4: intronic/intergenic
rs2295334	6	44003090	G>A	0.05	synonymous_variant	SCIRT, LINC03040	6e-18	Tier 4: intronic/intergenic
rs641153	6	31946403	G>A,C,T	0.101	missense_variant	CFB	1e-17	Tier 1: coding
rs10033900	4	109737911	T>C	0.05	intron_variant	CFI	5e-17	Tier 4: intronic/intergenic
rs11200638	10	122461028	G>A,T	0.36	non_coding_transcript_exon_variant	HTRA1, HTRA1-AS1	5e-17	Tier 4: intronic/intergenic
rs201459901	20	58078669	T>TA	0.05	intergenic_variant	LINC01742 - HSPD1P19	3e-16	Tier 4: intronic/intergenic
rs12019136	19	5835666	G>A	0.05	intron_variant	FUT6	2e-15	Tier 4: intronic/intergenic
rs2043085	15	58388755	T>A,C,G	0.05	intergenic_variant	ALDH1A2	4e-15	Tier 4: intronic/intergenic
rs62358361	5	39327786	G>C,T		intron_variant	C9	1e-14	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 53 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CFB	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
SKIC2	Orphanet:84064	Trichohepatoenteric syndrome
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TIMP3	Orphanet:59181	Sorsby fundus dystrophy
C2	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C3	Orphanet:280133	Complement component 3 deficiency
C3	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
C9	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency
SLC44A4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CFHR3	Orphanet:329931	C3 glomerulonephritis
TRPM3	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KMT2E	Orphanet:528084	Non-specific syndromic intellectual disability
CETP	Orphanet:181428	Familial Hyperalphalipoproteinemia
B3GLCT	Orphanet:709	Peters plus syndrome
COL4A3	Orphanet:653722	Digenic Alport syndrome
COL4A3	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
COL4A3	Orphanet:88918	Autosomal dominant Alport syndrome
COL4A3	Orphanet:88919	Autosomal recessive Alport syndrome
SPEF2	Orphanet:244	Primary ciliary dyskinesia
SPEF2	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency
GPX4	Orphanet:93317	Spondylometaphyseal dysplasia, Sedaghatian type
CFH	Orphanet:200421	Immunodeficiency with factor H anomaly
CFH	Orphanet:244242	HELLP syndrome
CFH	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFH	Orphanet:329903	Immunoglobulin-mediated membranoproliferative glomerulonephritis
CFH	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFH	Orphanet:75376	Familial drusen
CFH	Orphanet:93571	Dense deposit disease
CFHR1	Orphanet:329931	C3 glomerulonephritis
CFHR1	Orphanet:93571	Dense deposit disease
CFI	Orphanet:200418	Immunodeficiency with factor I anomaly
CFI	Orphanet:244242	HELLP syndrome
CFI	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFI	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFI	Orphanet:75376	Familial drusen
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia
LIPC	Orphanet:140905	Hyperlipidemia due to hepatic triacylglycerol lipase deficiency
MMP19	Orphanet:464760	Familial cavitary optic disc anomaly
MMP9	Orphanet:1040	Metaphyseal anadysplasia
NRTN	Orphanet:388	Hirschsprung disease
PRLR	Orphanet:397685	Familial hyperprolactinemia
HTRA1	Orphanet:199354	Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy
HTRA1	Orphanet:252128	Malignant peripheral nerve sheath tumor with perineurial differentiation
HTRA1	Orphanet:252212	Malignant triton tumor

Cohort genes → proteins

63 cohort genes, 59 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	63

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RORB	HGNC:10259	ENSG00000198963	Q92753	Nuclear receptor ROR-beta	gwas
CFB	HGNC:1037	ENSG00000243649	P00751	Complement factor B	gwas
SKIC2	HGNC:10898	ENSG00000204351	Q15477	Superkiller complex protein 2	gwas
SRPK2	HGNC:11306	ENSG00000135250	P78362	SRSF protein kinase 2	gwas
SYN3	HGNC:11496	ENSG00000185666	O14994	Synapsin-3	gwas
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	gwas
TIMP3	HGNC:11822	ENSG00000100234	P35625	Metalloproteinase inhibitor 3	gwas
TNFRSF10A	HGNC:11904	ENSG00000104689	O00220	Tumor necrosis factor receptor superfamily member 10A	gwas
TNR	HGNC:11953	ENSG00000116147	Q92752	Tenascin-R	gwas
C2	HGNC:1248	ENSG00000166278	P06681	Complement C2	gwas
VEGFA	HGNC:12680	ENSG00000112715	P15692	Vascular endothelial growth factor A, long form	gwas
VTN	HGNC:12724	ENSG00000109072	P04004	Vitronectin	gwas
C3	HGNC:1318	ENSG00000125730	P01024	Complement C3	gwas
MARK4	HGNC:13538	ENSG00000007047	Q96L34	MAP/microtubule affinity-regulating kinase 4	gwas
C9	HGNC:1358	ENSG00000113600	P02748	Complement component C9	gwas
SLC44A4	HGNC:13941	ENSG00000204385	Q53GD3	Choline transporter-like protein 4	gwas
CIMIP1	HGNC:16216	ENSG00000124237	Q9H1P6	Ciliary microtubule inner protein 1	gwas
SLC16A8	HGNC:16270	ENSG00000100156	O95907	Monocarboxylate transporter 3	gwas
CD63	HGNC:1692	ENSG00000135404	P08962	CD63 antigen	gwas
CFHR3	HGNC:16980	ENSG00000116785	Q02985	Complement factor H-related protein 3	gwas
TRPM3	HGNC:17992	ENSG00000083067	Q9HCF6	Transient receptor potential cation channel subfamily M member 3	gwas
NPLOC4	HGNC:18261	ENSG00000182446	Q8TAT6	Nuclear protein localization protein 4 homolog	gwas
PILRB	HGNC:18297	ENSG00000121716	Q9UKJ0	Paired immunoglobulin-like type 2 receptor beta	gwas
KMT2E	HGNC:18541	ENSG00000005483	Q8IZD2	Inactive histone-lysine N-methyltransferase 2E	gwas
CETP	HGNC:1869	ENSG00000087237	P11597	Cholesteryl ester transfer protein	gwas
B3GLCT	HGNC:20207	ENSG00000187676	Q6Y288	Beta-1,3-glucosyltransferase	gwas
PILRA	HGNC:20396	ENSG00000085514	Q9UKJ1	Paired immunoglobulin-like type 2 receptor alpha	gwas
ATF7IP2	HGNC:20397	ENSG00000166669	Q5U623	Activating transcription factor 7-interacting protein 2	gwas
CNN2	HGNC:2156	ENSG00000064666	Q99439	Calponin-2	gwas
ACAD10	HGNC:21597	ENSG00000111271	Q6JQN1	Acyl-CoA dehydrogenase family member 10	gwas
FGD6	HGNC:21740	ENSG00000180263	Q6ZV73	FYVE, RhoGEF and PH domain-containing protein 6	gwas
COL15A1	HGNC:2192	ENSG00000204291	P39059	Collagen alpha-1(XV) chain	gwas
COL4A3	HGNC:2204	ENSG00000169031	Q01955	Collagen alpha-3(IV) chain	gwas
COL8A1	HGNC:2215	ENSG00000144810	P27658	Collagen alpha-1(VIII) chain	gwas
ARHGAP21	HGNC:23725	ENSG00000107863	Q5T5U3	Rho GTPase-activating protein 21	gwas
CTRB1	HGNC:2521	ENSG00000168925	P17538	Chymotrypsinogen B	gwas
CTRB2	HGNC:2522	ENSG00000168928	Q6GPI1	Chymotrypsinogen B2	gwas
SPEF2	HGNC:26293	ENSG00000152582	Q9C093	Sperm flagellar protein 2	gwas
TMEM97	HGNC:28106	ENSG00000109084	Q5BJF2	Sigma intracellular receptor 2	gwas
LINC03040	HGNC:28692	ENSG00000181577	Q8N319	Uncharacterized protein LINC03040	gwas
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	gwas
TSPAN10	HGNC:29942	ENSG00000182612	Q9H1Z9	Tetraspanin-10	gwas
EXOC3L2	HGNC:30162	ENSG00000283632	Q2M3D2	Exocyst complex component 3-like protein 2	gwas
ARMS2	HGNC:32685	ENSG00000254636	P0C7Q2	Age-related maculopathy susceptibility protein 2	gwas
MIR548A2	HGNC:32797	ENSG00000207689		microRNA 548a-2	gwas
FUT6	HGNC:4017	ENSG00000156413	P51993	4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6	gwas
ADAMTS9-AS2	HGNC:42435	ENSG00000241684		ADAMTS9 antisense RNA 2	gwas
GPX4	HGNC:4556	ENSG00000167468	P36969	Phospholipid hydroperoxide glutathione peroxidase GPX4	gwas
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	gwas
CFHR1	HGNC:4888	ENSG00000244414	Q03591	Complement factor H-related protein 1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RORB	Nuclear receptor ROR-beta	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.
CFB	Complement factor B	Precursor of the catalytic component of the C3 and C5 convertase complexes of the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the…
SKIC2	Superkiller complex protein 2	Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.
SRPK2	SRSF protein kinase 2	Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splici…
SYN3	Synapsin-3	May be involved in the regulation of neurotransmitter release and synaptogenesis.
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
TIMP3	Metalloproteinase inhibitor 3	Mediates a variety of processes including matrix regulation and turnover, inflammation, and angiogenesis, through reversible inhibition of zinc protease superfamily enzymes, primarily matrix metalloproteinases (MMPs).
TNFRSF10A	Tumor necrosis factor receptor superfamily member 10A	Receptor for the cytotoxic ligand TNFSF10/TRAIL.
TNR	Tenascin-R	Neural extracellular matrix (ECM) protein involved in interactions with different cells and matrix components.
C2	Complement C2	Precursor of the catalytic component of the C3 and C5 convertase complexes, which are part of the complement pathway, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive i…
VEGFA	Vascular endothelial growth factor A, long form	Participates in the induction of key genes involved in the response to hypoxia and in the induction of angiogenesis such as HIF1A.
VTN	Vitronectin	Vitronectin is a cell adhesion and spreading factor found in serum and tissues.
C3	Complement C3	Precursor of non-enzymatic components of the classical, alternative, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adapt…
MARK4	MAP/microtubule affinity-regulating kinase 4	Serine/threonine-protein kinase.
C9	Complement component C9	Pore-forming component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis.
SLC44A4	Choline transporter-like protein 4	Choline transporter that plays a role in the choline-acetylcholine system and is required to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the prote…
SLC16A8	Monocarboxylate transporter 3	Probable retinal pigment epithelium (RPE)-specific proton-coupled L-lactate transporter.
CD63	CD63 antigen	Functions as a cell surface receptor for TIMP1 and plays a role in the activation of cellular signaling cascades.
CFHR3	Complement factor H-related protein 3	Might be involved in complement regulation.
TRPM3	Transient receptor potential cation channel subfamily M member 3	Constitutively active, non-selective divalent cation-conducting channel that is permeable to Ca(2+), Mn(2+), and Mg(2+), with a high permeability for Ca(2+).
NPLOC4	Nuclear protein localization protein 4 homolog	The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome.
PILRB	Paired immunoglobulin-like type 2 receptor beta	Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system.
KMT2E	Inactive histone-lysine N-methyltransferase 2E	Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription.
CETP	Cholesteryl ester transfer protein	Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles.
B3GLCT	Beta-1,3-glucosyltransferase	Beta-1,3-glucosyltransferase involved in one of the two pathways responsible for protein O-linked fucosylation, a unique post-translational modification of cysteine-knotted proteins that regulates various biological processes.
PILRA	Paired immunoglobulin-like type 2 receptor alpha	Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system.
ATF7IP2	Activating transcription factor 7-interacting protein 2	Recruiter that couples transcriptional factors to general transcription apparatus and thereby modulates transcription regulation and chromatin formation.
CNN2	Calponin-2	Thin filament-associated protein that is implicated in the regulation and modulation of smooth muscle contraction.
ACAD10	Acyl-CoA dehydrogenase family member 10	Acyl-CoA dehydrogenase only active with R- and S-2-methyl-C15-CoA.
FGD6	FYVE, RhoGEF and PH domain-containing protein 6	May activate CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP.
COL15A1	Collagen alpha-1(XV) chain	Structural protein that stabilizes microvessels and muscle cells, both in heart and in skeletal muscle.
COL4A3	Collagen alpha-3(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COL8A1	Collagen alpha-1(VIII) chain	Macromolecular component of the subendothelium.
ARHGAP21	Rho GTPase-activating protein 21	Functions as a GTPase-activating protein (GAP) for RHOA and CDC42.
SPEF2	Sperm flagellar protein 2	Required for correct axoneme development in spermatozoa.
TMEM97	Sigma intracellular receptor 2	Sigma-2 receptor which contributes to ameliorate dysfunctional cellular processes and slow degenerative progression by regulating cell functions including cholesterol biosynthesis/trafficking, membrane trafficking, autophagy, lipid membran…
ABCA1	Phospholipid-transporting ATPase ABCA1	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.
TSPAN10	Tetraspanin-10	Part of TspanC8 subgroup, composed of 6 members that interact with the transmembrane metalloprotease ADAM10.
FUT6	4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6	Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the N-acetyl glucosamine (GlcNAc) of a distal alpha2,3 sialylated lactosamine unit of a glycoprotein- or a glycolipid-linked sialopolylactosamines chain or…
GPX4	Phospholipid hydroperoxide glutathione peroxidase GPX4	Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins.
CFH	Complement factor H	Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.
CFHR1	Complement factor H-related protein 1	Involved in complement regulation.
CFI	Complement factor I	Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways.
APOE	Apolipoprotein E	APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids.
LIPC	Hepatic triacylglycerol lipase	Catalyzes the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins, including chylomicrons, intermediate density lipoproteins (IDL), low density lipoproteins (LDL) of large size and high density lipoprot…
MMP19	Matrix metalloproteinase-19	Endopeptidase that degrades various components of the extracellular matrix, such as aggrecan and cartilage oligomeric matrix protein (comp), during development, haemostasis and pathological conditions (arthritic disease).
MMP9	Matrix metalloproteinase-9	Matrix metalloproteinase that plays an essential role in local proteolysis of the extracellular matrix and in leukocyte migration.
NRTN	Neurturin	Growth factor that supports the survival of sympathetic neurons in culture.
PRLR	Prolactin receptor	This is a receptor for the anterior pituitary hormone prolactin (PRL).
HTRA1	Serine protease HTRA1	Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin.

Protein-family classification

Druggable: 28 · Difficult: 5 · Unknown: 30 · Druggable fraction: 0.44

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
Complement	5	21.3×	4e-05
Protease	8	4.7×	0.002
Nuclear receptor	1	6.1×	0.356
Transporter	2	2.5×	0.356
Antibody/Immunoglobulin	4	1.9×	0.356
Kinase	4	1.8×	0.356
Ion channel	1	1.8×	0.681
Other/Unknown	30	0.8×	0.986
Enzyme (other)	3	0.6×	0.986
Scaffold/PPI	2	0.6×	0.986
Transcription factor	3	0.4×	0.986

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RORB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
CFB	Protease	yes	3.4.21.47	Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
SKIC2	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Ski2/MTR4_C
SRPK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SYN3	Other/Unknown	no		Synapsin, ATP_grasp_subdomain_1, PreATP-grasp_dom_sf
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
TIMP3	Other/Unknown	no		Netrin_domain, TIMP, TIMP-like_OB-fold
TNFRSF10A	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, DEATH-like_dom_sf
TNR	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
C2	Protease	yes		Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
VEGFA	Other/Unknown	no		PDGF/VEGF_dom, PD_growth_factor_CS, VEGF_C
VTN	Other/Unknown	no		Hemopexin-like_dom, Somatomedin_B_dom, Hemopexin_CS
C3	Complement	yes	3.4.21.47	Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
MARK4	Kinase	yes		Prot_kinase_dom, KA1_dom, Ser/Thr_kinase_AS
C9	Complement	yes		TSP1_rpt, MAC_perforin, LDrepeatLR_classA_rpt
SLC44A4	Other/Unknown	no		Choline_transptr-like
CIMIP1	Other/Unknown	no		C20orf85-like
SLC16A8	Transporter	yes		MCT, MFS, MFS_dom
CD63	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
CFHR3	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
TRPM3	Ion channel	yes		Ion_trans_dom, TRPM_tetra, TRPM_tetra_sf
NPLOC4	Transcription factor	no		Znf_RanBP2, NPL4_Zn-bd_put, NPL4_C
PILRB	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig-like_fold
KMT2E	Transcription factor	no		SET_dom, Znf_PHD, Znf_FYVE_PHD
CETP	Other/Unknown	no		Lipid-bd_serum_glycop_C, Cholesteryl_ester_transfer, Lipid-bd_serum_glycop_N
B3GLCT	Other/Unknown	no		Fringe-like_glycosylTrfase, Nucleotide-diphossugar_trans
PILRA	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
ATF7IP2	Other/Unknown	no		FN3_dom, ATF7-int, ATF7IP_BD
CNN2	Other/Unknown	no		Calponin_repeat, CH_dom, Calponin/LIMCH1
ACAD10	Kinase	yes		Aminoglycoside_PTrfase, AcylCoA_DH/ox_M, HAD-SF_hydro_IA
FGD6	Transcription factor	no		DH_dom, Znf_FYVE, PH_domain
COL15A1	Other/Unknown	no		Collagen, Collagenase_NC10/endostatin, ConA-like_dom_sf
COL4A3	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL8A1	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
ARHGAP21	Scaffold/PPI	no		RhoGAP_dom, PDZ, PH_domain
CTRB1	Protease	yes		Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
CTRB2	Protease	yes		Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
SPEF2	Other/Unknown	no		CH_dom, CH_2, EF-hand-dom_pair
TMEM97	Other/Unknown	no		Sigma2_recept, EXPERA, Sigma-2_receptor-like
LINC03040	Other/Unknown	no		DUF5550
ABCA1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
TSPAN10	Other/Unknown	no		Tetraspanin_EC2_sf, Tetraspanin/Peripherin, Tetraspanin_CS
EXOC3L2	Other/Unknown	no		EXOC3/Sec6, EXOC3/Sec6_C
ARMS2	Other/Unknown	no
MIR548A2	Other/Unknown	no
FUT6	Enzyme (other)	yes	2.4.1.152	Glyco_trans_10, Glyco_tran_10_N, GT10-like_C_sf
ADAMTS9-AS2	Other/Unknown	no
GPX4	Enzyme (other)	yes	1.11.1.12	Glutathione_peroxidase, GPX_AS, GPX_CS
CFH	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
CFHR1	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	1
broad (>20)	61
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	12
liver	8
pigmented layer of retina	6
male germ line stem cell (sensu Vertebrata) in testis	6
buccal mucosa cell	4
placenta	4
right uterine tube	4
stromal cell of endometrium	3
tendon of biceps brachii	3
apex of heart	3
left testis	3
right testis	3
calcaneal tendon	3
granulocyte	3
secondary oocyte	3
body of pancreas	3
sural nerve	3
endothelial cell	2
gall bladder	2
cortical plate	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RORB	196	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
CFB	134	broad	marker	right lobe of liver, liver, gall bladder
SKIC2	134	ubiquitous	yes	right lobe of liver, pituitary gland, adenohypophysis
SRPK2	293	ubiquitous	marker	sperm, male germ cell, pons
SYN3	176	broad	marker	primordial germ cell in gonad, cortical plate, primary visual cortex
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
TIMP3	299	ubiquitous	marker	synovial joint, decidua, pigmented layer of retina
TNFRSF10A	230	ubiquitous	marker	buccal mucosa cell, nipple, pancreatic ductal cell
TNR	109	tissue_specific	marker	CA1 field of hippocampus, entorhinal cortex, inferior vagus X ganglion
C2	138	ubiquitous	marker	liver, right lobe of liver, placenta
VEGFA	297	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
VTN	132	broad	marker	right lobe of liver, liver, right adrenal gland
C3	289	ubiquitous	marker	parietal pleura, right lobe of liver, palpebral conjunctiva
MARK4	285	ubiquitous	yes	cortical plate, cervix squamous epithelium, lateral nuclear group of thalamus
C9	119	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
SLC44A4	130	tissue_specific	marker	mucosa of transverse colon, right uterine tube, rectum
CIMIP1	85	tissue_specific	marker	bronchial epithelial cell, bronchus, right uterine tube
SLC16A8	169	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, nucleus accumbens
CD63	305	ubiquitous	marker	stromal cell of endometrium, tendon of biceps brachii, adult organism
CFHR3	127	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
TRPM3	193	broad	marker	pigmented layer of retina, dorsal motor nucleus of vagus nerve, medial globus pallidus
NPLOC4	281	ubiquitous	marker	gastrocnemius, muscle of leg, apex of heart
PILRB	134	tissue_specific	yes	right testis, left testis, right uterine tube
KMT2E	264	ubiquitous	marker	tendon of biceps brachii, tendon, mucosa of paranasal sinus
CETP	165	broad	marker	lymph node, spleen, liver
B3GLCT	218	ubiquitous	marker	left ventricle myocardium, calcaneal tendon, cardiac muscle of right atrium
PILRA	217	broad	marker	monocyte, granulocyte, leukocyte
ATF7IP2	254	ubiquitous	marker	right testis, left testis, testis
CNN2	246	ubiquitous	marker	granulocyte, stromal cell of endometrium, right ovary
ACAD10	271	ubiquitous	marker	apex of heart, right lobe of liver, parotid gland

Protein interactions among cohort

Intra-cohort edges: 73.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793
MMP9	6,708
TGFBR1	4,828
BCAR1	4,469
SRPK2	3,839
ABCA1	3,551
CD63	3,521
CNN2	3,477
C3	3,199
GPX4	3,036

Intra-cohort edges

A	B	Sources
ABCA1	APOE	string_interaction
ABCA1	CETP	string_interaction
ABCA1	LIPC	string_interaction
ACAD10	CIMIP1	string_interaction
APOE	C9	biogrid_interaction, intact, string_interaction
APOE	CETP	string_interaction
APOE	CFH	string_interaction
APOE	EXOC3L2	string_interaction
APOE	LIPC	string_interaction
ARMS2	B3GLCT	string_interaction
ARMS2	C2	string_interaction
ARMS2	C3	string_interaction
ARMS2	CETP	string_interaction
ARMS2	CFB	string_interaction
ARMS2	CFH	string_interaction
ARMS2	CFHR1	string_interaction
ARMS2	CFHR3	string_interaction
ARMS2	CFI	string_interaction
ARMS2	COL8A1	string_interaction
ARMS2	HTRA1	string_interaction
ARMS2	LIPC	string_interaction
ARMS2	PILRB	string_interaction
ARMS2	SKIC2	string_interaction
ARMS2	SLC16A8	string_interaction
ARMS2	TSPAN10	string_interaction
B3GLCT	CIMIP1	string_interaction
B3GLCT	COL8A1	string_interaction
B3GLCT	RAD51B	string_interaction
B3GLCT	SLC16A8	string_interaction
B3GLCT	TSPAN10	string_interaction
C2	C3	string_interaction
C2	C9	string_interaction
C2	CFH	string_interaction
C2	CFHR1	string_interaction
C2	CFHR3	string_interaction
C2	CFI	string_interaction
C2	SKIC2	string_interaction
C3	C9	string_interaction
C3	CFB	intact, string_interaction
C3	CFH	biogrid_interaction, intact, string_interaction
C3	CFHR1	string_interaction
C3	CFHR3	biogrid_interaction, string_interaction
C3	CFI	biogrid_interaction, intact, string_interaction
C9	CFB	string_interaction
C9	CFH	string_interaction
C9	CFI	string_interaction
CETP	LIPC	string_interaction
CFB	CFHR1	intact, string_interaction
CFB	CFHR3	string_interaction
CFB	CFI	string_interaction

Structural data

PDB: 39 · AlphaFold-only: 20 · No structure: 4

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75
VEGFA	P15692	56
CFH	P08603	51
TGFBR1	P36897	44
APOE	P02649	29
MMP9	P14780	29
CFB	P00751	26
GPX4	P36969	23
HTRA1	Q92743	18
C2	P06681	14
PRLR	P16471	12
SKIC2	Q15477	11
VTN	P04004	9
C9	P02748	9
ABCA1	O95477	7
NRTN	Q99748	7
NPLOC4	Q8TAT6	6
PILRA	Q9UKJ1	6
BCAR1	P56945	5
RAD51B	O15315	5
SRPK2	P78362	3
KMT2E	Q8IZD2	3
CETP	P11597	3
ARHGAP21	Q5T5U3	3
TNR	Q92752	2
MARK4	Q96L34	2
CD63	P08962	2
PILRB	Q9UKJ0	2
COL4A3	Q01955	2
CFHR1	Q03591	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RDH5	Q92781	96.02
CFHR3	Q02985	91.93
CTRB1	P17538	91.90
CTRB2	Q6GPI1	91.79
TMEM97	Q5BJF2	90.27
FUT6	P51993	89.81
B3GLCT	Q6Y288	86.94
ACAD10	Q6JQN1	86.83
SLC44A4	Q53GD3	83.79
LIPC	P11150	82.03
MMP19	Q99542	79.70
RORB	Q92753	79.48
SLC16A8	O95907	77.38
CIMIP1	Q9H1P6	76.63
EXOC3L2	Q2M3D2	74.26
SPEF2	Q9C093	71.30
ARMS2	P0C7Q2	58.14
COL8A1	P27658	58.10
ATF7IP2	Q5U623	56.88
LINC03040	Q8N319	49.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 219. Enrichment computed across 63 evidence-associated genes (49 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 49 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of Complement cascade	9	42.8×	9e-11	CFB, C2, VTN, C3, C9, CFHR3, CFH, CFHR1 (+1 more)
Activation of C3 and C5	3	77.7×	6e-04	CFB, C2, C3
Collagen degradation	5	17.9×	6e-04	COL15A1, COL4A3, COL8A1, MMP19, MMP9
Assembly of collagen fibrils and other multimeric structures	4	16.4×	0.005	COL15A1, COL4A3, COL8A1, MMP9
Alternative complement activation	2	93.2×	0.007	CFB, C3
Chylomicron clearance	2	93.2×	0.007	APOE, LIPC
Activation of Matrix Metalloproteinases	3	18.9×	0.014	CTRB1, CTRB2, MMP9
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	3	18.9×	0.014	CETP, ABCA1, APOE
HDL remodeling	2	46.6×	0.017	CETP, APOE
Uptake of dietary cobalamins into enterocytes	2	46.6×	0.017	CTRB1, CTRB2
Collagen chain trimerization	3	15.9×	0.017	COL15A1, COL4A3, COL8A1
Plasma lipoprotein assembly, remodeling, and clearance	3	14.0×	0.023	ABCA1, APOE, LIPC
Plasma lipoprotein assembly	2	29.1×	0.035	ABCA1, APOE
Collagen biosynthesis and modifying enzymes	3	10.4×	0.046	COL15A1, COL4A3, COL8A1
Plasma lipoprotein remodeling	2	19.4×	0.060	APOE, LIPC
Plasma lipoprotein clearance	2	19.4×	0.060	APOE, LIPC
ECM proteoglycans	3	9.2×	0.060	TNR, VTN, COL4A3
Integrin cell surface interactions	3	8.2×	0.070	VTN, COL4A3, COL8A1
NR1H2 and NR1H3-mediated signaling	2	16.1×	0.078	ABCA1, APOE
Defective ABCA1 causes TGD	1	116.5×	0.085	ABCA1
Defective visual phototransduction due to RDH5 loss of function	1	116.5×	0.085	RDH5
Degradation of the extracellular matrix	3	7.2×	0.085	MMP19, MMP9, HTRA1
Loss of Function of TGFBR2 in Cancer	1	77.7×	0.108	TGFBR1
TGFBR2 Kinase Domain Mutants in Cancer	1	77.7×	0.108	TGFBR1
Biosynthesis of aspirin-triggered D-series resolvins	1	77.7×	0.108	GPX4
Signaling by Nuclear Receptors	3	6.2×	0.108	ABCA1, APOE, MMP9
TGFBR1 LBD Mutants in Cancer	1	58.3×	0.120	TGFBR1
Biosynthesis of D-series resolvins	1	58.3×	0.120	GPX4
Biosynthesis of E-series 18(R)-resolvins	1	58.3×	0.120	GPX4
Signaling by PDGF	2	10.4×	0.120	COL4A3, BCAR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 57 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
complement activation	7	76.7×	2e-09	CFB, C2, C3, C9, CFHR3, CFH, CFHR1
complement activation, alternative pathway	4	69.6×	7e-05	CFB, C3, C9, CFH
reverse cholesterol transport	4	65.7×	7e-05	CETP, ABCA1, APOE, LIPC
very-low-density lipoprotein particle remodeling	3	110.9×	3e-04	CETP, APOE, LIPC
complement activation, classical pathway	4	38.1×	4e-04	C2, C3, C9, CFI
complement activation, GZMK pathway	3	68.2×	0.001	C2, C3, C9
low-density lipoprotein particle remodeling	3	55.4×	0.002	CETP, APOE, LIPC
activation of transmembrane receptor protein tyrosine kinase activity	2	197.1×	0.002	PILRB, PRLR
cholesterol homeostasis	5	13.7×	0.002	CETP, TMEM97, ABCA1, APOE, LIPC
proteolysis	9	5.4×	0.002	CFB, C2, CTRB1, CTRB2, CFH, CFI, MMP19, MMP9 (+1 more)
high-density lipoprotein particle remodeling	3	42.2×	0.003	CETP, APOE, LIPC
artery morphogenesis	3	35.5×	0.004	TGFBR1, VEGFA, APOE
protein O-linked glycosylation via fucose	2	118.3×	0.005	B3GLCT, FUT6
positive regulation of lipoprotein transport	2	118.3×	0.005	TMEM97, APOE
chylomicron remnant clearance	2	98.5×	0.006	APOE, LIPC
lipoprotein biosynthetic process	2	98.5×	0.006	ABCA1, APOE
endodermal cell differentiation	3	26.1×	0.007	VTN, COL8A1, MMP9
triglyceride homeostasis	3	25.3×	0.007	CETP, APOE, LIPC
cholesterol metabolic process	4	13.8×	0.007	CETP, ABCA1, APOE, LIPC
response to bacterium	4	13.6×	0.007	CFB, C2, C3, PRLR
positive regulation of apoptotic cell clearance	2	84.5×	0.007	C2, C3
coronary artery morphogenesis	2	65.7×	0.011	TGFBR1, VEGFA
high-density lipoprotein particle assembly	2	59.1×	0.013	ABCA1, APOE
regulation of Cdc42 protein signal transduction	2	49.3×	0.018	ABCA1, APOE
negative regulation of macrophage derived foam cell differentiation	2	45.5×	0.019	CETP, ABCA1
positive regulation of integrin-mediated signaling pathway	2	45.5×	0.019	VTN, CD63
regulation of cell adhesion	3	16.1×	0.019	TNR, VTN, PRLR
negative regulation of blood coagulation	2	42.2×	0.021	VTN, APOE
phospholipid efflux	2	39.4×	0.022	ABCA1, APOE
positive regulation of vascular endothelial growth factor signaling pathway	2	39.4×	0.022	VEGFA, VTN

Therapeutics

Drugs indicated for this disease

7 approved, 1 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)
Bevacizumab Gamma	Approved (phase 4)
Brolucizumab	Approved (phase 4)
Faricimab	Approved (phase 4)
Pegaptanib Sodium	Approved (phase 4)
Ranibizumab	Approved (phase 4)
Verteporfin	Approved (phase 4)
Bevacizumab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Conbercept, Dexamethasone, Dorzolamide, Tarcocimab Tedromer, Timolol, Triamcinolone, Triamcinolone Acetonide.

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 14 · Phased (≥1): 15 · Undrugged: 48

Druggability breadth: 34 of 63 evidence-associated genes (54%) 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
RORB	TRETINOIN
CFB	IPTACOPAN
SRPK2	FEDRATINIB
TGFBR1	MOMELOTINIB
VEGFA	VADADUSTAT
MARK4	RIVASTIGMINE TARTRATE
ACAD10	GEFITINIB
CTRB1	BORTEZOMIB
TMEM97	PENTAZOCINE
LIPC	ORLISTAT
MMP9	CHLOROXINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM97	48	4
TGFBR1	28	4
MMP9	26	4
MARK4	22	4
SRPK2	11	4
ACAD10	7	4
CTRB1	7	4
VEGFA	5	4
CETP	5	3
RORB	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORB
IPTACOPAN	4	CFB
FEDRATINIB	4	MARK4, SRPK2
ALECTINIB	4	SRPK2
NINTEDANIB	4	MARK4, SRPK2, TGFBR1
SUNITINIB	4	MARK4, SRPK2
MIDOSTAURIN	4	MARK4, SRPK2
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
DASATINIB	4	TGFBR1
CRIZOTINIB	4	TGFBR1
VADADUSTAT	4	VEGFA
BELZUTIFAN	4	VEGFA
RIVASTIGMINE TARTRATE	4	MARK4
DONEPEZIL	4	MARK4
GEFITINIB	4	ACAD10
BORTEZOMIB	4	CTRB1
PENTAZOCINE	4	TMEM97
INDACATEROL	4	TMEM97
NEFAZODONE HYDROCHLORIDE	4	TMEM97
DIHYDROERGOTAMINE MESYLATE	4	TMEM97
CINACALCET HYDROCHLORIDE	4	TMEM97
AZELASTINE HYDROCHLORIDE	4	TMEM97
DOLUTEGRAVIR	4	TMEM97
SALMETEROL	4	TMEM97
TEGASEROD MALEATE	4	TMEM97
HYDROXYCHLOROQUINE	4	TMEM97
VILAZODONE HYDROCHLORIDE	4	TMEM97
CLEMASTINE	4	TMEM97
KETOTIFEN FUMARATE	4	TMEM97

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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

Symbol	Assays	Type breakdown
MMP9	713	Binding:685, ADMET:20, Functional:8
TGFBR1	541	Binding:516, Functional:13, ADMET:12
MARK4	246	Binding:245, Functional:1
SRPK2	221	Binding:221
TMEM97	200	Binding:197, ADMET:3
GPX4	176	Binding:176
CTRB1	140	Binding:109, ADMET:24, Functional:6, Toxicity:1
CETP	132	Binding:127, Functional:5
RORB	90	Binding:87, Functional:3
VEGFA	64	Binding:64
CTRB2	56	Binding:30, ADMET:24, Functional:1, Toxicity:1
CFB	33	Binding:33
HTRA1	28	Binding:28
C3	15	Binding:15
LIPC	12	Binding:11, ADMET:1
CNN2	9	Binding:9
FUT6	6	Binding:6
C2	4	Binding:4
MMP19	4	ADMET:2, Binding:1, Toxicity:1
TNFRSF10A	3	Binding:3
CD63	3	Binding:3
ACAD10	3	Binding:3
SLC16A8	2	Binding:2
TRPM3	2	Binding:2
ABCA1	2	Binding:2
TIMP3	1	Binding:1
VTN	1	Binding:1
C9	1	Binding:1
KMT2E	1	Binding:1
CFH	1	Binding:1
PRLR	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFB	3.4.21.47	alternative-complement-pathway C3/C5 convertase
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase
FUT6	2.4.1.152, 2.4.1.65	4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase, 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase
GPX4	1.11.1.12	phospholipid-hydroperoxide glutathione peroxidase
CFI	3.4.21.45	complement factor I
MMP9	3.4.24.35	gelatinase B
HTRA1	3.4.21.107, 3.4.21.108	peptidase Do, HtrA2 peptidase
RDH5	1.1.1.300, 1.1.1.315	NADP-retinol dehydrogenase, 11-cis-retinol dehydrogenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SRPK2	221
TGFBR1	541
MARK4	246
CETP	132
CTRB1	140
TMEM97	200
GPX4	176
MMP9	713

Pharmacogenomics

Cohort genes with a PharmGKB record: 61; 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)
TRETINOIN	4	RORB
IPTACOPAN	4	CFB
FEDRATINIB	4	MARK4, SRPK2
ALECTINIB	4	SRPK2
NINTEDANIB	4	MARK4, SRPK2, TGFBR1
SUNITINIB	4	MARK4, SRPK2
MIDOSTAURIN	4	MARK4, SRPK2
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
DASATINIB	4	TGFBR1
CRIZOTINIB	4	TGFBR1
VADADUSTAT	4	VEGFA
BELZUTIFAN	4	VEGFA
RIVASTIGMINE TARTRATE	4	MARK4
DONEPEZIL	4	MARK4
GEFITINIB	4	ACAD10
BORTEZOMIB	4	CTRB1
PENTAZOCINE	4	TMEM97
INDACATEROL	4	TMEM97
NEFAZODONE HYDROCHLORIDE	4	TMEM97
DIHYDROERGOTAMINE MESYLATE	4	TMEM97
CINACALCET HYDROCHLORIDE	4	TMEM97
AZELASTINE HYDROCHLORIDE	4	TMEM97
DOLUTEGRAVIR	4	TMEM97
SALMETEROL	4	TMEM97
TEGASEROD MALEATE	4	TMEM97
HYDROXYCHLOROQUINE	4	TMEM97
VILAZODONE HYDROCHLORIDE	4	TMEM97
CLEMASTINE	4	TMEM97
KETOTIFEN FUMARATE	4	TMEM97

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	RORB, CFB, SRPK2, TGFBR1, VEGFA, MARK4, ACAD10, CTRB1, TMEM97, LIPC (+1 more)
B	Phased (≥1) drug, not yet approved	4	TIMP3, CD63, CETP, CTRB2
C	Druggable family + PDB, no drug	14	TNR, C2, C3, C9, TRPM3, PILRB, PILRA, ABCA1, GPX4, CFH (+4 more)
D	Druggable family + AlphaFold only, no drug	5	SLC16A8, CFHR3, FUT6, MMP19, RDH5
E	Difficult family or no structure, no drug	29	SKIC2, SYN3, TNFRSF10A, VTN, SLC44A4, CIMIP1, NPLOC4, KMT2E, B3GLCT, ATF7IP2 (+19 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C3	15	CFB
CFHR3	0	CFB
EXOC3L2	0	MARK4
ARMS2	0	CFB
CFHR1	0	CFB
CFI	0	CFB
GPX4	176	—
SKIC2	0	—
SYN3	0	—
TNFRSF10A	3	—
TNR	0	—
C2	4	—
VTN	1	—
C9	1	—
SLC44A4	0	—
CIMIP1	0	—
SLC16A8	2	—
TRPM3	2	—
NPLOC4	0	—
PILRB	0	—
KMT2E	1	—
B3GLCT	0	—
PILRA	0	—
ATF7IP2	0	—
CNN2	9	—
FGD6	0	—
COL15A1	0	—
COL4A3	0	—
COL8A1	0	—
ARHGAP21	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 119.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	35
PHASE3	26
PHASE2	18
PHASE1	13
PHASE4	11
PHASE1/PHASE2	8
PHASE2/PHASE3	7
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06875245	PHASE4	RECRUITING	Comparing Efficacy of 8-Week and 12-Week Faricimab Initial Follow-Up Treatment Intervals
NCT01896284	PHASE4	COMPLETED	Study to Evaluate Efficacy of Aflibercept in Neovascular Age-related Macular Degeneration Patients Non Responders to Anti-Vascular Endothelial Growth Factor
NCT01986907	PHASE4	COMPLETED	Safety and Tolerability of Ranibizumab in Mono/Bilateral Wet Age Related Macular Degeneration (w-AMD) Patients in Eyes With BCVA<2/10 and/or 2nd Affected Eye
NCT02060604	PHASE4	COMPLETED	Pilot Study of Ranibizumab With and Without Ketorolac Eyedrops for Exudative Age-related Macular Degeneration
NCT02257632	PHASE4	COMPLETED	Systemic Vascular Endothelial Growth Factor (VEGF) Protein Dynamics Following Intravitreal Injections of Ranibizumab Versus Aflibercept in Patients With Neovascular Age-related Macular Degeneration
NCT02305238	PHASE4	COMPLETED	Japanese Treat and Extend Study of Aflibercept in Neovascular Age-related Macular Degeneration
NCT02689518	PHASE4	COMPLETED	EAGLE: Evaluating Genotypes Using Intravitreal Aflibercept Injection
NCT02806752	PHASE4	UNKNOWN	Intravitreal Ranibizumab and TA Combination Therapy vs. Ranibizumab Monotherapy in Polypoidal Choroidal Vasculopathy
NCT02944227	PHASE4	COMPLETED	Efficacy of Fixed Monthly Dosing of Ranibizumab in Neovascular Age-related Macular Degeneration
NCT03022292	PHASE4	COMPLETED	The IAI-OCTA Study; a Study of OCT-Angiography Analysis Efficacy
NCT04698850	PHASE4	WITHDRAWN	Brolucizumab vs. Aflibercept for Retinal Angiomatous Proliferation
NCT04704921	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Pivotal 1 Study of ABBV-RGX-314 (Also Known as RGX-314) Gene Therapy Administered Via Subretinal Delivery One Time in Participants With nAMD
NCT05112861	PHASE3	ACTIVE_NOT_RECRUITING	A 3-month Study to Compare the Safety of ONS-5010 in Vials Versus Pre-filled Syringe in Subjects With Visual Impairment Due to Retinal Disorders
NCT05407636	PHASE3	RECRUITING	Pivotal 2 Study of RGX-314 Gene Therapy in Participants With nAMD
NCT06556368	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Tarcocimab Tedromer and Tabirafusp Tedromer Compared to Aflibercept in Participants With Neovascular (Wet) Age-related Macular Degeneration (wAMD) - DAYBREAK
NCT06668064	PHASE3	ACTIVE_NOT_RECRUITING	A 2-year Study of EYP-1901 in Subjects With Wet Age Related Macular Degeneration (wAMD) (LUGANO) Primary Efficacy Will be Determined at Week 56
NCT06683742	PHASE3	ACTIVE_NOT_RECRUITING	A 2-year Study of EYP-1901 in Subjects With Wet Age Related Macular Degeneration (wAMD) (LUCIA) Primary Efficacy Will be Determined at Week 56
NCT06856577	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety Study of Ixoberogene Soroparvovec (Ixo-vec) in Participants With Neovascular Age-Related Macular Degeneration
NCT06952452	PHASE3	RECRUITING	Pharmacogenomics of antiVEGF in Patients With Age-Associated Macular Degeneration (AMD)
NCT07317934	PHASE3	RECRUITING	Efficacy and Safety of LX102 Gene Therapy in Patients With Neovascular Age-related Macular Degeneration (nAMD) (STELLAR)
NCT07440225	PHASE2/PHASE3	RECRUITING	A Clinical Trial of EYE201/MK-8748 in People With Macular Degeneration (MK-8748-002)
NCT07482176	PHASE3	RECRUITING	Efficacy and Safety Study of Ixoberogene Soroparvovec (Ixo-vec) in Participants With Neovascular Age-related Macular Degeneration (AQUARIUS)
NCT07496567	PHASE2/PHASE3	RECRUITING	A Clinical Trial of EYE201/MK-8748 in People With Macular Degeneration (MK-8748-003)
NCT00139282	PHASE3	TERMINATED	A Safety and Efficacy Study of Squalamine Lactate for Injection (MSI-1256F) for Wet Age-Related Macular Degeneration
NCT00590694	PHASE2/PHASE3	COMPLETED	Lucentis for Age-related Macular Degeneration Pigment Epithelial Detachments
NCT02036723	PHASE3	WITHDRAWN	Safety and Efficacy Study of BCD-021 Compared to Lucentis® in Patients With Neovascular Wet Age-related Macular Degeneration
NCT02157077	PHASE3	COMPLETED	Aflibercept After Ranibizumab in Exudative Age-related Macular Degeneration
NCT03034772	PHASE2/PHASE3	COMPLETED	Dorzolamide-timolol in Combination With Anti-vascular Endothelial Growth Factor Injections for Wet Age-related Macular Degeneration
NCT03823287	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Faricimab in Participants With Neovascular Age-Related Macular Degeneration (TENAYA)
NCT03823300	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Faricimab in Participants With Neovascular Age-Related Macular Degeneration (LUCERNE)
NCT03834753	PHASE3	COMPLETED	A Clinical Effectiveness Study Examining the Efficacy and Safety of ONS-5010 in Subjects With Neovascular Age-related Macular Degeneration (AMD)
NCT03844074	PHASE3	COMPLETED	A Clinical Effectiveness Study Examining the Efficacy and Safety of ONS-5010 in Subjects With Neovascular Age-related Macular Degeneration (AMD)
NCT03954626	PHASE3	COMPLETED	Study to Collect Safety and ECG Data on Brolucizumab 6 mg Intravitreal Treatment in Patients With Wet AMD
NCT04049266	PHASE2/PHASE3	TERMINATED	A Study to Evaluate the Efficacy and Safety of KSI-301, an Anti-VEGF Antibody Biopolymer Conjugate, Versus Aflibercept in Patients With Neovascular (Wet) Age-Related Macular Degeneration.
NCT04113538	PHASE3	UNKNOWN	Treat and Extend Analysis Trial With Aflibercept in Wet-AMD
NCT04480463	PHASE3	COMPLETED	A Study to Comparing SCD411 and Eylea® in Subjects With Wet Age-related Macular Degeneration (AMD)
NCT04516278	PHASE3	COMPLETED	A 3-month Study to Assess the Safety of ONS-5010 in Subjects With Visual Impairment Due to Retinal Disorders
NCT04964089	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared With Intravitreal Aflibercept in Participants With Neovascular (Wet) Age-related Macular Degeneration (wAMD)
NCT05297292	PHASE2/PHASE3	UNKNOWN	A Study to Evaluate the Efficacy and Safety of MW02 in the Treatment of nAMD
NCT05345236	PHASE3	COMPLETED	A Study to Compare QL1207 to Eylea® in Subjects With Wet Age-related Macular Degeneration (wAMD)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AFLIBERCEPT	4	33
RANIBIZUMAB	4	6
FARICIMAB	4	3
KETOROLAC	4	3
BROLUCIZUMAB	4	2
CANAKINUMAB	4	1
DOXYCYCLINE HYCLATE	4	1
TRIAMCINOLONE ACETONIDE	4	1
TARCOCIMAB TEDROMER	3	4
ABICIPAR PEGOL	3	1
SQUALAMINE LACTATE	3	1
VATALANIB	3	1
IXOBEROGENE SOROPARVOVEC	2	2
LAZUCIRNON	2	2
TEDROMER	1	1
CHEMBL1200567	0	1