Age-related macular degeneration

Summary

Age-related macular degeneration (MONDO:0005150) is a disease (an umbrella term covering 15 Mondo subtypes) with 75 cohort genes (512 GWAS associations across 65 studies) and 679 clinical trials. The dominant Reactome pathway is Regulation of Complement cascade (13 cohort genes). Top therapeutic interventions include ranibizumab, aflibercept, and brolucizumab.

At a glance

• Umbrella term: 15 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 512
• ClinVar variants: 13
• Clinical trials: 679

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	age-related macular degeneration
Mondo ID	MONDO:0005150
EFO	EFO:0001365
OMIM	603075
Orphanet	279
DOID	DOID:10871
ICD-11	1514301548
NCIT	C84391
SNOMED CT	267718000
UMLS	C0242383
MedGen	116576
GARD	0027715
Is cancer (heuristic)	no

Also known as: age-related macular degeneration · AMD · ARMD · macular degeneration, age-related · Senile macular retinal degeneration

Data availability: 13 ClinVar variants · 512 GWAS associations (65 studies) · 151 cell lines.

Disease family

An umbrella term covering 15 Mondo subtypes.

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

Related subtypes (5): hole retinal cyst, cystoid macular retinal degeneration, preretinal fibrosis, toxic maculopathy, retinal drusen

Subtypes (15): wet macular degeneration, 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

512 GWAS associations across 65 studies. Top hits map to 14 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1329424	1e-323	CFH	T	0.59
rs10490924	4e-322	HTRA1-AS1, ARMS2	T	2.94
rs36212732	5e-316	ARMS2, HTRA1-AS1	A	0.6
rs2248799	6e-300	HTRA1	?	0.28
rs2672598	4e-291	HTRA1-AS1, HTRA1	?	0.28
rs60642321	4e-291	CFHR1 - CFHR4	?	0.44
rs5016801	2e-274	CFH	?	0.4
rs1061170	1e-261	CFH	C	2.41
rs11200629	7e-221	HTRA1-AS1	?	0.24
rs6585827	9e-221	PLEKHA1	?	0.24
rs61818925	6e-165	CFHR1 - CFHR4	?	1.67
rs3750846	3e-161	HTRA1-AS1, ARMS2	?	2.48
rs12116643	2e-157	CFHR5	T	1.67
rs3750847	1e-116	ARMS2, HTRA1-AS1	T	1.47
rs4658046	3e-114	CFH	C	1.38
rs10922109	5e-114	CFH	?
rs1410996	2e-111	CFH	?
rs116503776	1e-103	SKIC2	?	1.75
rs6677089	1e-102	CFH	?	0.37
rs522162	6e-92	NELFE	?	0.35
rs429608	4e-89	SKIC2	G	1.74
chr10:124215315	6e-85		?
rs488380	2e-84	CFH	T	0.6
rs10737680	2e-76	CFH	A	3.11
rs2284665	2e-74	HTRA1	?	2.26
chr1:196660995	2e-72		?
rs11569415	2e-71	C3	?	0.15
rs2230199	4e-69	C3	?	1.43
chr1:196679455	7e-69		?
rs187328863	1e-68	KCNT2	?	2.27

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90250837	Chung J	2022	38,984	1,662,607	Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes.
GCST010284	Han X	2020	37,342	92,890	Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration.
GCST90250832	Chung J	2022	16,144	1,401,064	Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes.
GCST90250833	Chung J	2022	16,144	1,895,495	Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes.
GCST90250834	Chung J	2022	16,144	1,662,607	Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes.
GCST004868	Persad PJ	2017	16,144	17,832	Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.
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.
GCST004870	Persad PJ	2017	16,122	17,810	Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.
GCST004872	Persad PJ	2017	16,042	17,734	Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.
GCST004871	Persad PJ	2017	15,413	16,351	Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	7
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	42

MAF distribution

Bucket	Variants
common (>=0.05)	42
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	8

Functional consequences

Consequence	Count
intron_variant	32
missense_variant	7
unknown	5
non_coding_transcript_exon_variant	2
synonymous_variant	2
intergenic_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs10490924	10	122454932	G>C,T	0.3	missense_variant	HTRA1-AS1, ARMS2		Tier 1: coding
rs10737680	1	196710325	A>C,T	0.36	intron_variant	CFH		Tier 4: intronic/intergenic
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
rs800292	1	196673103	G>A,C,T	0.23	missense_variant	CFH		Tier 1: coding
rs7542235	1	196854483	A>G	0.19	intron_variant	CFHR1 - CFHR4		Tier 4: intronic/intergenic
rs2248799	10	122464428	C>A,G,T	0.49	intron_variant	HTRA1		Tier 4: intronic/intergenic
rs1329424	1	196677046	T>A,C,G	0.38	intron_variant	CFH	1e-323	Tier 4: intronic/intergenic
rs36212732	10	122455682	A>G	0.21	intron_variant	ARMS2, HTRA1-AS1	5e-316	Tier 4: intronic/intergenic
rs2672598	10	122461166	T>A,C	0.05	non_coding_transcript_exon_variant	HTRA1-AS1, HTRA1	4e-291	Tier 4: intronic/intergenic
rs60642321	1	196853238	A>G,T	0.05	intron_variant	CFHR1 - CFHR4	4e-291	Tier 4: intronic/intergenic
rs5016801	1	196665380	A>G	0.05	intron_variant	CFH	2e-274	Tier 4: intronic/intergenic
rs1061170	1	196690107	C>A,G,T	0.37	missense_variant	CFH	1e-261	Tier 1: coding
rs11200629	10	122439069	A>G	0.05	intron_variant	HTRA1-AS1	7e-221	Tier 4: intronic/intergenic
rs6585827	10	122406099	G>A,C	0.05	intron_variant	PLEKHA1	9e-221	Tier 4: intronic/intergenic
rs61818925	1	196846320	T>A,G	0.05	intergenic_variant	CFHR1 - CFHR4	6e-165	Tier 4: intronic/intergenic
rs12116643	1	197004053	T>C,G	0.16	intron_variant	CFHR5	2e-157	Tier 4: intronic/intergenic
rs3750847	10	122455905	C>A,G,T	0.22	intron_variant	ARMS2, HTRA1-AS1	1e-116	Tier 4: intronic/intergenic
rs4658046	1	196701627	C>A,G,T	0.39	intron_variant	CFH	3e-114	Tier 4: intronic/intergenic
rs1410996	1	196727803	G>A,C,T	0.05	intron_variant	CFH	2e-111	Tier 4: intronic/intergenic
rs116503776	6	31962685			intron_variant	SKIC2	1e-103	Tier 4: intronic/intergenic
rs6677089	1	196715183	A>C,G	0.05	intron_variant	CFH	1e-102	Tier 4: intronic/intergenic
rs522162	6	31952140	T>A,C,G	0.05	3_prime_UTR_variant	NELFE	6e-92	Tier 2: splice/UTR
rs429608	6	31962685	G>A	0.14	intron_variant	SKIC2	4e-89	Tier 4: intronic/intergenic
chr10:124215315							6e-85	Tier 4: intronic/intergenic
rs488380	1	196695375	C>A,G,T	0.377	intron_variant	CFH	2e-84	Tier 4: intronic/intergenic
rs2284665	10	122467114	G>A,C,T	0.05	intron_variant	HTRA1	2e-74	Tier 4: intronic/intergenic
chr1:196660995							2e-72	Tier 4: intronic/intergenic
rs11569415	19	6716268	G>A	0.05	intron_variant	C3	2e-71	Tier 4: intronic/intergenic

ClinVar germline variants

13 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 conflicting classifications of pathogenicity, 1 pathogenic; risk factor, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
99304	NM_000350.3(ABCA4):c.4594G>A (p.Asp1532Asn)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5065	NC_000001.10:g.(196722206_?)_(?_196808505)del	CFHR1	Pathogenic; risk factor	no assertion criteria provided
5479	NM_006329.4(FBLN5):c.259C>T (p.Pro87Ser)	FBLN5	Conflicting classifications of pathogenicity	no assertion criteria provided
5480	NM_006329.4(FBLN5):c.506T>C (p.Ile169Thr)	FBLN5	Conflicting classifications of pathogenicity	no assertion criteria provided
5482	NM_006329.4(FBLN5):c.1087G>A (p.Ala363Thr)	FBLN5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7879	NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala)	ABCA4	Uncertain significance	reviewed by expert panel
1030095	NM_006329.4(FBLN5):c.143C>T (p.Thr48Ile)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2664436	NM_006329.4(FBLN5):c.371A>C (p.Gln124Pro)	FBLN5	Uncertain significance	no assertion criteria provided
502499	NM_006329.4(FBLN5):c.799G>A (p.Gly267Ser)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
5477	NM_006329.4(FBLN5):c.178G>C (p.Val60Leu)	FBLN5	Uncertain significance	criteria provided, single submitter
5478	NM_006329.4(FBLN5):c.212G>A (p.Arg71Gln)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
5481	NM_006329.4(FBLN5):c.1051C>T (p.Arg351Trp)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
5483	NM_006329.4(FBLN5):c.1235G>A (p.Gly412Glu)	FBLN5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 40 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

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

Gene	HGNC	Evidence routes
CFHR1	CFHR1	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CFHR1	Orphanet:329931	C3 glomerulonephritis
CFHR1	Orphanet:93571	Dense deposit disease
RLBP1	Orphanet:227796	Fundus albipunctatus
RLBP1	Orphanet:52427	Retinitis punctata albescens
RLBP1	Orphanet:791	Retinitis pigmentosa
RLBP1	Orphanet:85128	Bothnia retinal dystrophy
CFB	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
RREB1	Orphanet:567	22q11.2 deletion syndrome
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
TNXB	Orphanet:230839	Classical-like Ehlers-Danlos syndrome type 1
TNXB	Orphanet:289365	Familial vesicoureteral reflux
TYR	Orphanet:352734	Minimal pigment oculocutaneous albinism type 1
TYR	Orphanet:352737	Temperature-sensitive oculocutaneous albinism type 1
TYR	Orphanet:79431	Oculocutaneous albinism type 1A
TYR	Orphanet:79434	Oculocutaneous albinism type 1B
TYR	Orphanet:895	Waardenburg syndrome type 2
C2	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
UQCRFS1	Orphanet:1460	Isolated complex III deficiency
C3	Orphanet:280133	Complement component 3 deficiency
C3	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
ADAMTS9	Orphanet:93592	Juvenile nephronophthisis
C9	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency
CFHR3	Orphanet:329931	C3 glomerulonephritis
TRPM3	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
TOMM40	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
KMT2E	Orphanet:528084	Non-specific syndromic intellectual disability
CETP	Orphanet:181428	Familial Hyperalphalipoproteinemia
ASPM	Orphanet:2512	Autosomal recessive primary microcephaly
B3GLCT	Orphanet:709	Peters plus syndrome
COL10A1	Orphanet:174	Metaphyseal chondrodysplasia, Schmid type
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
CFHR5	Orphanet:329931	C3 glomerulonephritis

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	74
gwas_and_clinvar	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CFHR1	HGNC:4888	ENSG00000244414	Q03591	Complement factor H-related protein 1	gwas,clinvar
RLBP1	HGNC:10024	ENSG00000140522	P12271	Retinaldehyde-binding protein 1	gwas
RORB	HGNC:10259	ENSG00000198963	Q92753	Nuclear receptor ROR-beta	gwas
CFB	HGNC:1037	ENSG00000243649	P00751	Complement factor B	gwas
RREB1	HGNC:10449	ENSG00000124782	Q92766	Ras-responsive element-binding protein 1	gwas
SKIC2	HGNC:10898	ENSG00000204351	Q15477	Superkiller complex protein 2	gwas
SRPK2	HGNC:11306	ENSG00000135250	P78362	SRSF protein kinase 2	gwas
WHR1	HGNC:11398	ENSG00000204344	P49842	Winged helix repair factor 1	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
TNXB	HGNC:11976	ENSG00000168477	P22105	Tenascin-X	gwas
TRPC4	HGNC:12336	ENSG00000133107	Q9UBN4	Short transient receptor potential channel 4	gwas
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	gwas
C2	HGNC:1248	ENSG00000166278	P06681	Complement C2	gwas
UQCRFS1	HGNC:12587	ENSG00000169021	P47985	Cytochrome b-c1 complex subunit Rieske, mitochondrial	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
ADAMTS9	HGNC:13202	ENSG00000163638	Q9P2N4	A disintegrin and metalloproteinase with thrombospondin motifs 9	gwas
CDH22	HGNC:13251	ENSG00000149654	Q9UJ99	Cadherin-22	gwas
MARK4	HGNC:13538	ENSG00000007047	Q96L34	MAP/microtubule affinity-regulating kinase 4	gwas
C9	HGNC:1358	ENSG00000113600	P02748	Complement component C9	gwas
ATP6V0D1	HGNC:13724	ENSG00000159720	P61421	V-type proton ATPase subunit d 1	gwas
NELFE	HGNC:13974	ENSG00000204356	P18615	Negative elongation factor E	gwas
PLEKHA1	HGNC:14335	ENSG00000107679	Q9HB21	Pleckstrin homology domain-containing family A member 1	gwas
SNX7	HGNC:14971	ENSG00000162627	Q9UNH6	Sorting nexin-7	gwas
CIMIP1	HGNC:16216	ENSG00000124237	Q9H1P6	Ciliary microtubule inner protein 1	gwas
SLC16A8	HGNC:16270	ENSG00000100156	O95907	Monocarboxylate transporter 3	gwas
CD34	HGNC:1662	ENSG00000174059	P28906	Hematopoietic progenitor cell antigen CD34	gwas
PKNOX2	HGNC:16714	ENSG00000165495	Q96KN3	Homeobox protein PKNOX2	gwas
CD63	HGNC:1692	ENSG00000135404	P08962	CD63 antigen	gwas
POSTN	HGNC:16953	ENSG00000133110	Q15063	Periostin	gwas
CFHR4	HGNC:16979	ENSG00000134365	Q92496	Complement factor H-related protein 4	gwas
CFHR3	HGNC:16980	ENSG00000116785	Q02985	Complement factor H-related protein 3	gwas
DPF3	HGNC:17427	ENSG00000205683	Q92784	Zinc finger protein DPF3	gwas
NMRK2	HGNC:17871	ENSG00000077009	Q9NPI5	Nicotinamide riboside kinase 2	gwas
TRPM3	HGNC:17992	ENSG00000083067	Q9HCF6	Transient receptor potential cation channel subfamily M member 3	gwas
TOMM40	HGNC:18001	ENSG00000130204	O96008	Mitochondrial import receptor subunit TOM40 homolog	gwas
KHDRBS3	HGNC:18117	ENSG00000131773	O75525	KH domain-containing, RNA-binding, signal transduction-associated protein 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
ABHD2	HGNC:18717	ENSG00000140526	P08910	Monoacylglycerol lipase ABHD2	gwas
CNTNAP5	HGNC:18748	ENSG00000155052	Q8WYK1	Contactin-associated protein-like 5	gwas
KCNT2	HGNC:18866	ENSG00000162687	Q6UVM3	Potassium channel subfamily T member 2	gwas
ASPM	HGNC:19048	ENSG00000066279	Q8IZT6	Abnormal spindle-like microcephaly-associated protein	gwas
SDK1	HGNC:19307	ENSG00000146555	Q7Z5N4	Protein sidekick-1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CFHR1	Complement factor H-related protein 1	Involved in complement regulation.
RLBP1	Retinaldehyde-binding protein 1	Soluble retinoid carrier essential the proper function of both rod and cone photoreceptors.
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…
RREB1	Ras-responsive element-binding protein 1	Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters.
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…
WHR1	Winged helix repair factor 1	DNA-binding protein which is required for efficient transcription-coupled nucleotide excision repair (TC-NER).
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.
TNXB	Tenascin-X	Appears to mediate interactions between cells and the extracellular matrix.
TRPC4	Short transient receptor potential channel 4	Forms a receptor-activated non-selective calcium permeant cation channel.
TYR	Tyrosinase	This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds.
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…
UQCRFS1	Cytochrome b-c1 complex subunit Rieske, mitochondrial	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
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…
ADAMTS9	A disintegrin and metalloproteinase with thrombospondin motifs 9	Cleaves the large aggregating proteoglycans, aggrecan (at the ‘1838-Glu-|-Ala-1839’ site) and versican (at the ‘1428-Glu-|-Ala-1429’ site).
CDH22	Cadherin-22	Cadherins are calcium-dependent cell adhesion proteins.
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.
ATP6V0D1	V-type proton ATPase subunit d 1	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
NELFE	Negative elongation factor E	Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II.
PLEKHA1	Pleckstrin homology domain-containing family A member 1	Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides.
SNX7	Sorting nexin-7	Involved in the regulation of endocytosis and in several stages of intracellular trafficking.
SLC16A8	Monocarboxylate transporter 3	Probable retinal pigment epithelium (RPE)-specific proton-coupled L-lactate transporter.
CD34	Hematopoietic progenitor cell antigen CD34	Possible adhesion molecule with a role in early hematopoiesis by mediating the attachment of stem cells to the bone marrow extracellular matrix or directly to stromal cells.
CD63	CD63 antigen	Functions as a cell surface receptor for TIMP1 and plays a role in the activation of cellular signaling cascades.
POSTN	Periostin	Induces cell attachment and spreading and plays a role in cell adhesion.
CFHR4	Complement factor H-related protein 4	Involved in complement regulation.
CFHR3	Complement factor H-related protein 3	Might be involved in complement regulation.
DPF3	Zinc finger protein DPF3	Belongs to the neuron-specific chromatin remodeling complex (nBAF complex).
NMRK2	Nicotinamide riboside kinase 2	Catalyzes the phosphorylation of nicotinamide riboside (NR) and nicotinic acid riboside (NaR) to form nicotinamide mononucleotide (NMN) and nicotinic acid mononucleotide (NaMN).
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+).
TOMM40	Mitochondrial import receptor subunit TOM40 homolog	Channel-forming protein that forms part of the translocase of the outer mitochondrial membrane (TOM) complex essential for the recognition and translocation of cytosolically synthesized mitochondrial preproteins.
KHDRBS3	KH domain-containing, RNA-binding, signal transduction-associated protein 3	RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion.
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.
ABHD2	Monoacylglycerol lipase ABHD2	Progesterone-dependent acylglycerol lipase that catalyzes hydrolysis of endocannabinoid arachidonoylglycerol (AG) from cell membrane.
CNTNAP5	Contactin-associated protein-like 5	May play a role in the correct development and proper functioning of the peripheral and central nervous system and be involved in cell adhesion and intercellular communication.
KCNT2	Potassium channel subfamily T member 2	Sodium-activated and chloride-activated potassium channel.
ASPM	Abnormal spindle-like microcephaly-associated protein	Involved in mitotic spindle regulation and coordination of mitotic processes.
SDK1	Protein sidekick-1	Adhesion molecule that promotes lamina-specific synaptic connections in the retina.
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.

Protein-family classification

Druggable: 30 · Difficult: 11 · Unknown: 34 · Druggable fraction: 0.4

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	6	21.4×	4e-06
Antibody/Immunoglobulin	7	2.7×	0.085
Ion channel	3	4.5×	0.120
Protease	5	2.4×	0.163
Nuclear receptor	1	5.2×	0.425
Kinase	4	1.5×	0.571
Transporter	1	1.0×	0.989
Transcription factor	8	0.9×	0.989
Other/Unknown	34	0.8×	0.989
Scaffold/PPI	3	0.7×	0.989
Enzyme (other)	2	0.3×	0.989
GPCR	1	0.3×	0.989

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CFHR1	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
RLBP1	Other/Unknown	no		CRAL-TRIO_dom, CRAL/TRIO_N_dom, CRAL/TRIO_N_dom_sf
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
RREB1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, RREB1
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
WHR1	Other/Unknown	no		STK19-like
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
TNXB	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
TRPC4	Ion channel	yes		Ankyrin_rpt, TRPC_channel, TRPC4_channel
TYR	Enzyme (other)	yes	1.14.18.1	Tyrosinase_Cu-bd, Di-copper_centre_dom_sf, Tyrosinase/Hemocyanin
C2	Protease	yes		Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
UQCRFS1	Other/Unknown	no		Rieske_TM, Rieske_Fe-S_prot_C, Ubiquinol_cyt_c_Rdtase_Fe-S-su
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
ADAMTS9	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
CDH22	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
MARK4	Kinase	yes		Prot_kinase_dom, KA1_dom, Ser/Thr_kinase_AS
C9	Complement	yes		TSP1_rpt, MAC_perforin, LDrepeatLR_classA_rpt
ATP6V0D1	Other/Unknown	no		ATPase_V0-cplx_csu/dsu, ATPase_V0-cplx_dsu, V-type_ATPase_csu/dsu
NELFE	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, NELFE
PLEKHA1	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, PI-Interact_SigTrans_Reg
SNX7	Scaffold/PPI	no		PX_dom, AH/BAR_dom_sf, PX_dom_sf
CIMIP1	Other/Unknown	no		C20orf85-like
SLC16A8	Transporter	yes		MCT, MFS, MFS_dom
CD34	Other/Unknown	no		CD34, CD34/Podocalyxin
PKNOX2	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
CD63	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
POSTN	Other/Unknown	no		FAS1_domain, EMI_domain, TGFBI/POSTN
CFHR4	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
CFHR3	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
DPF3	Transcription factor	no		Znf_PHD, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
NMRK2	Enzyme (other)	yes	2.7.1.173	P-loop_NTPase
TRPM3	Ion channel	yes		Ion_trans_dom, TRPM_tetra, TRPM_tetra_sf
TOMM40	Other/Unknown	no		Porin_dom_sf, Porin_Euk/Tom40, Tom40
KHDRBS3	Other/Unknown	no		KH_dom, Sam68-YY, Qua1_dom
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
ABHD2	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_4_CS, ABHD4
CNTNAP5	Other/Unknown	no		FA58C, EGF, Laminin_G
KCNT2	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
ASPM	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, CH_dom, ARM-like
SDK1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	74
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	11
liver	9
pigmented layer of retina	9
male germ line stem cell (sensu Vertebrata) in testis	8
buccal mucosa cell	5
apex of heart	5
Brodmann (1909) area 23	4
right adrenal gland	4
cortical plate	4
synovial joint	4
tendon of biceps brachii	4
endothelial cell	3
sperm	3
tibia	3
visceral pleura	3
decidua	3
stromal cell of endometrium	3
mucosa of transverse colon	3
lateral nuclear group of thalamus	3
left testis	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CFHR1	125		marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
RLBP1	126	tissue_specific	marker	pigmented layer of retina, retina, optic choroid
RORB	196	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
CFB	134	broad	marker	right lobe of liver, liver, gall bladder
RREB1	278	ubiquitous	marker	buccal mucosa cell, epithelium of nasopharynx, oral cavity
SKIC2	134	ubiquitous	yes	right lobe of liver, pituitary gland, adenohypophysis
SRPK2	293	ubiquitous	marker	sperm, male germ cell, pons
WHR1	134	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland
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
TNXB	134	ubiquitous	marker	apex of heart, right adrenal gland cortex, right adrenal gland
TRPC4	158	broad	yes	stromal cell of endometrium, decidua, smooth muscle tissue
TYR	59	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, upper leg skin
C2	138	ubiquitous	marker	liver, right lobe of liver, placenta
UQCRFS1	134	ubiquitous	marker	gastrocnemius, heart left ventricle, mucosa of transverse colon
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
ADAMTS9	236	broad	marker	omental fat pad, peritoneum, sural nerve
CDH22	149	broad	marker	cerebellar vermis, paraflocculus, right hemisphere of cerebellum
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
ATP6V0D1	297	ubiquitous	marker	mucosa of transverse colon, type B pancreatic cell, lateral nuclear group of thalamus
NELFE	134	ubiquitous	marker	left testis, right testis, testis
PLEKHA1	280	ubiquitous	marker	upper leg skin, sperm, Brodmann (1909) area 23
SNX7	281	ubiquitous	marker	tibia, synovial joint, cartilage tissue
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

Protein interactions among cohort

Intra-cohort edges: 52.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD34	4,928
TGFBR1	4,828
UQCRFS1	4,001
SRPK2	3,839
TYR	3,663
POSTN	3,600
CD63	3,521
CNN2	3,477
TOMM40	3,210
C3	3,199

Intra-cohort edges

A	B	Sources
ACAD10	CIMIP1	string_interaction
ADAMTS9	B3GLCT	string_interaction
ADAMTS9	COL8A1	string_interaction
ADAMTS9	FILIP1L	string_interaction
ASPM	SNX7	biogrid_interaction
ATF6B	TNXB	string_interaction
B3GLCT	CIMIP1	string_interaction
B3GLCT	COL8A1	string_interaction
B3GLCT	FILIP1L	string_interaction
B3GLCT	SLC16A8	string_interaction
C2	C3	string_interaction
C2	C9	string_interaction
C2	CFHR1	string_interaction
C2	CFHR3	string_interaction
C2	PLEKHA1	string_interaction
C2	SKIC2	string_interaction
C2	WHR1	string_interaction
C3	C9	string_interaction
C3	CFB	intact, string_interaction
C3	CFHR1	string_interaction
C3	CFHR3	biogrid_interaction, string_interaction
C3	CFHR4	biogrid_interaction, intact, string_interaction
C3	CFHR5	string_interaction
C9	CFB	string_interaction
CFB	CFHR1	intact, string_interaction
CFB	CFHR3	string_interaction
CFB	CFHR4	intact, string_interaction
CFB	CFHR5	string_interaction
CFHR1	CFHR5	intact
CFHR1	PLEKHA1	string_interaction
CFHR1	ZBTB41	string_interaction
CFHR3	PLEKHA1	string_interaction
CFHR4	KCNT2	string_interaction
CFHR4	ZBTB41	string_interaction
CFHR5	ZBTB41	string_interaction
CIMIP1	PILRB	string_interaction
CIMIP1	SLC16A8	string_interaction
CNTN4	CNTNAP5	string_interaction
COL8A1	FILIP1L	string_interaction
COL8A1	SLC16A8	string_interaction
COL8A1	TGFBR1	string_interaction
CTRB1	CTRB2	biogrid_interaction, intact
FILIP1L	SLC16A8	string_interaction
FILIP1L	TGFBR1	string_interaction
KCNT2	TNFRSF10A	biogrid_interaction
KCNT2	ZBTB41	string_interaction
KHDRBS3	MARK4	biogrid_interaction, intact
KMT2E	SRPK2	string_interaction
NELFE	SKIC2	string_interaction
PILRA	PILRB	biogrid_interaction, intact, string_interaction

Structural data

PDB: 44 · AlphaFold-only: 30 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C3	P01024	75
VEGFA	P15692	56
TGFBR1	P36897	44
CFB	P00751	26
NELFE	P18615	15
C2	P06681	14
ACKR3	P25106	14
TOMM40	O96008	12
SKIC2	Q15477	11
VTN	P04004	9
C9	P02748	9
ATP6V0D1	P61421	9
DPF3	Q92784	8
NPLOC4	Q8TAT6	6
PILRA	Q9UKJ1	6
WHR1	P49842	5
UQCRFS1	P47985	5
KHDRBS3	O75525	5
RLBP1	P12271	4
SRPK2	P78362	3
TNXB	P22105	3
TRPC4	Q9UBN4	3
POSTN	Q15063	3
KMT2E	Q8IZD2	3
CETP	P11597	3
ARHGAP21	Q5T5U3	3
CFHR1	Q03591	2
MARK4	Q96L34	2
CD63	P08962	2
PILRB	Q9UKJ0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CFHR3	Q02985	91.93
CTRB1	P17538	91.90
CTRB2	Q6GPI1	91.79
ABHD2	P08910	91.06
NMRK2	Q9NPI5	88.56
CFHR4	Q92496	87.75
B3GLCT	Q6Y288	86.94
ACAD10	Q6JQN1	86.83
CNTN4	Q8IWV2	86.72
CNTN6	Q9UQ52	86.19
KCTD14	Q9BQ13	86.09
CNTNAP5	Q8WYK1	84.06
CFHR5	Q9BXR6	83.76
RORB	Q92753	79.48
LRATD2	Q96KN1	78.97
SLC16A8	O95907	77.38
CIMIP1	Q9H1P6	76.63
KCNT2	Q6UVM3	76.42
CDH22	Q9UJ99	76.19
SDK1	Q7Z5N4	72.92
ADAMTS9	Q9P2N4	69.47
FILIP1L	Q4L180	68.64
ZBTB41	Q5SVQ8	61.91
PKNOX2	Q96KN3	61.38
CD34	P28906	60.99
COL8A1	P27658	58.10
ATF6B	Q99941	55.31
STOX2	Q9P2F5	50.30
RREB1	Q92766	48.28
ASPM	Q8IZT6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 393. Enrichment computed across 140 evidence-associated genes (102 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 102 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	13	29.7×	8e-14	CFHR1, CFB, C2, VTN, C3, C9, CFHR4, CFHR3 (+5 more)
Collagen degradation	6	10.3×	0.005	COL10A1, COL15A1, COL4A3, COL8A1, MMP19, MMP9
Activation of C3 and C5	3	37.3×	0.007	CFB, C2, C3
Defective visual phototransduction due to RDH5 loss of function	2	112.0×	0.008	RLBP1, RDH5
Assembly of collagen fibrils and other multimeric structures	5	9.8×	0.012	COL10A1, COL15A1, COL4A3, COL8A1, MMP9
Alternative complement activation	2	44.8×	0.038	CFB, C3
Chylomicron clearance	2	44.8×	0.038	APOE, LIPC
Collagen chain trimerization	4	10.2×	0.038	COL10A1, COL15A1, COL4A3, COL8A1
The canonical retinoid cycle in rods (twilight vision)	3	15.3×	0.041	RLBP1, ABCA4, RDH5
GLI proteins bind promoters of Hh responsive genes to promote transcription	2	32.0×	0.063	GLI2, GLI3
TRP channels	3	12.0×	0.069	TRPC4, TRPM3, TRPM1
HDL remodeling	2	22.4×	0.095	CETP, APOE
Uptake of dietary cobalamins into enterocytes	2	22.4×	0.095	CTRB1, CTRB2
Collagen biosynthesis and modifying enzymes	4	6.7×	0.095	COL10A1, COL15A1, COL4A3, COL8A1
Activation of Matrix Metalloproteinases	3	9.1×	0.106	CTRB1, CTRB2, MMP9
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	3	9.1×	0.106	CETP, ABCA1, APOE
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	4.3×	0.146	C3, CD34, PILRB, PILRA, NECTIN2
Integrin cell surface interactions	4	5.3×	0.153	VTN, COL10A1, COL4A3, COL8A1
Defective visual phototransduction due to ABCA4 loss of function	1	112.0×	0.176	ABCA4
Plasma lipoprotein assembly	2	14.0×	0.176	ABCA1, APOE
Complement cascade	2	12.4×	0.181	MBL2, CD46
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	2	12.4×	0.181	KCTD15, APOE
Plasma lipoprotein assembly, remodeling, and clearance	3	6.7×	0.181	ABCA1, APOE, LIPC
Degradation of the extracellular matrix	4	4.6×	0.181	ADAMTS9, MMP19, MMP9, HTRA1
Initial triggering of complement	2	11.8×	0.192	C2, MBL2
Signaling by PTK6	2	10.7×	0.216	KHDRBS3, BCAR1
Signaling by Non-Receptor Tyrosine Kinases	2	10.7×	0.216	KHDRBS3, BCAR1
SDK interactions	1	56.0×	0.227	SDK1
Defective ABCA1 causes TGD	1	56.0×	0.227	ABCA1
Abortive elongation of HIV-1 transcript in the absence of Tat	2	9.7×	0.227	NELFE, POLR2B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 128 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	10	48.8×	3e-12	CFHR1, CFB, C2, C3, C9, CFHR4, CFHR3, CFHR5 (+2 more)
complement activation, alternative pathway	5	38.7×	5e-05	CFB, C3, C9, CFHR5, CFH
complement activation, classical pathway	6	25.5×	5e-05	C2, C3, C9, CFI, MBL2, CD46
reverse cholesterol transport	4	29.3×	0.002	CETP, ABCA1, APOE, LIPC
very-low-density lipoprotein particle remodeling	3	49.4×	0.003	CETP, APOE, LIPC
obsolete cytolysis by host of symbiont cells	3	49.4×	0.003	CFHR1, CFHR5, CFHR2
camera-type eye morphogenesis	4	23.9×	0.003	VEGFA, ADAMTS9, COL8A1, GLI3
smooth muscle cell-matrix adhesion	2	131.7×	0.007	VTN, DDR1
response to bacterium	6	9.1×	0.007	CFB, C2, C3, ADAMTS9, STOX2, PRLR
complement activation, GZMK pathway	3	30.4×	0.012	C2, C3, C9
activation of transmembrane receptor protein tyrosine kinase activity	2	87.8×	0.014	PILRB, PRLR
positive regulation of vascular endothelial growth factor signaling pathway	3	26.3×	0.014	TNXB, VEGFA, VTN
cell adhesion	12	3.5×	0.014	TNXB, VTN, POSTN, CNTNAP5, CNTN6, COL15A1, COL4A3, COL8A1 (+4 more)
low-density lipoprotein particle remodeling	3	24.7×	0.015	CETP, APOE, LIPC
visual perception	8	5.0×	0.015	RLBP1, RORB, TIMP3, TYR, BBS9, ABCA4, TRPM1, RDH5
mammary gland alveolus development	3	23.2×	0.017	VEGFA, DDR1, PRLR
hindgut morphogenesis	2	65.8×	0.021	GLI2, GLI3
luteolysis	2	52.7×	0.026	MMP19, NOTCH4
protein O-linked glycosylation via fucose	2	52.7×	0.026	B3GLCT, FUT6
positive regulation of lipoprotein transport	2	52.7×	0.026	TMEM97, APOE
high-density lipoprotein particle remodeling	3	18.8×	0.026	CETP, APOE, LIPC
embryo implantation	4	11.0×	0.026	DDR1, IGFBP7, MMP9, PRLR
developmental growth	3	17.2×	0.030	ASPM, GLI2, GLI3
chylomicron remnant clearance	2	43.9×	0.033	APOE, LIPC
lipoprotein biosynthetic process	2	43.9×	0.033	ABCA1, APOE
artery morphogenesis	3	15.8×	0.033	TGFBR1, VEGFA, APOE
cell surface receptor protein tyrosine kinase signaling pathway	5	6.8×	0.033	PILRB, DDR1, FRK, NRTN, BCAR1
negative regulation of protein binding	3	14.6×	0.040	CFHR1, CFHR5, CFHR2
cell-matrix adhesion	5	6.4×	0.040	TNXB, VTN, CD34, CD63, FBLN5
positive regulation of apoptotic cell clearance	2	37.6×	0.040	C2, C3

Therapeutics

Drugs indicated for this disease

1 approved, 17 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Verteporfin	Approved (phase 4)
Abicipar Pegol	Phase 3 (in late-stage trials)
Acetylcysteine	Phase 3 (in late-stage trials)
Aflibercept	Phase 3 (in late-stage trials)
Anecortave Acetate	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Bevacizumab	Phase 3 (in late-stage trials)
Bevasiranib	Phase 3 (in late-stage trials)
Brolucizumab	Phase 3 (in late-stage trials)
Clopidogrel	Phase 3 (in late-stage trials)
Conbercept	Phase 3 (in late-stage trials)
Elamipretide	Phase 3 (in late-stage trials)
Faricimab	Phase 3 (in late-stage trials)
Pegaptanib Sodium	Phase 3 (in late-stage trials)
Pegpleranib Sodium	Phase 3 (in late-stage trials)
Ranibizumab	Phase 3 (in late-stage trials)
Sozinibercept	Phase 3 (in late-stage trials)
Triamcinolone Acetonide	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANTI-GD2 MONOCLONAL ANTIBODY 3F8, Adalimumab, Alteplase, Atorvastatin, Avacincaptad Pegol, Avacincaptad Pegol Sodium, Bromfenac, CM-082, Carotuximab, Curcumin, Daclizumab, Dexamethasone, Dorzolamide, Eculizumab, Emixustat, Everolimus, Fluocinolone Acetonide, Infliximab, Iptacopan, Levodopa, Linifanib, Mecamylamine, Minocycline, Mycophenolate Mofetil, Polidocanol, Propranolol, Quercetin, Resveratrol, Sirolimus, Sodium Chloride, Spironolactone, Tacrolimus Anhydrous, Timolol, Unoprostone Isopropyl.

Drug target analysis

Approved (phase 4): 9 · Phase ≥3: 12 · Phased (≥1): 15 · Undrugged: 60

Druggability breadth: 56 of 140 evidence-associated genes (40%) 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
TYR	ASCORBIC ACID
VEGFA	VADADUSTAT
MARK4	RIVASTIGMINE TARTRATE
ACAD10	GEFITINIB
CTRB1	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBR1	28	4
MARK4	22	4
SRPK2	11	4
TYR	10	4
ACAD10	7	4
CTRB1	7	4
VEGFA	5	4
CETP	5	3
RORB	2	4
CD63	2	2

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
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
VADADUSTAT	4	VEGFA
BELZUTIFAN	4	VEGFA
RIVASTIGMINE TARTRATE	4	MARK4
DONEPEZIL	4	MARK4
GEFITINIB	4	ACAD10
BORTEZOMIB	4	CTRB1
DOVITINIB	3	MARK4, SRPK2
LESTAURTINIB	3	MARK4, SRPK2, TGFBR1
RUBOXISTAURIN	3	SRPK2
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
SURAMIN	3	TIMP3
CURCUMIN	3	TYR
RESVERATROL	3	TYR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
MARK4	246	Binding:245, Functional:1
SRPK2	221	Binding:221
TYR	211	Binding:209, ADMET:2
CTRB1	140	Binding:109, ADMET:24, Functional:6, Toxicity:1
CETP	132	Binding:127, Functional:5
ACKR3	102	Binding:77, Functional:24, ADMET:1
RORB	90	Binding:87, Functional:3
VEGFA	64	Binding:64
CTRB2	56	Binding:30, ADMET:24, Functional:1, Toxicity:1
WHR1	36	Binding:36
CFB	33	Binding:33
TRPC4	22	Binding:18, ADMET:4
C3	15	Binding:15
CNN2	9	Binding:9
LSM14A	8	Binding:8
KCNT2	7	Binding:7
C2	4	Binding:4
TNFRSF10A	3	Binding:3
CD63	3	Binding:3
TOMM40	3	Binding:3
ACAD10	3	Binding:3
SLC16A8	2	Binding:2
TRPM3	2	Binding:2
TIMP3	1	Binding:1
VTN	1	Binding:1
C9	1	Binding:1
PLEKHA1	1	Binding:1
KMT2E	1	Binding:1
FOXK1	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
TYR	1.14.18.1	tyrosinase
C3	3.4.21.47	alternative-complement-pathway C3/C5 convertase
NMRK2	2.7.1.173, 2.7.1.22	nicotinate riboside kinase, ribosylnicotinamide kinase

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
TYR	211
MARK4	246
CETP	132
ACKR3	102
CTRB1	140

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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
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
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
VADADUSTAT	4	VEGFA
BELZUTIFAN	4	VEGFA
RIVASTIGMINE TARTRATE	4	MARK4
DONEPEZIL	4	MARK4
GEFITINIB	4	ACAD10
BORTEZOMIB	4	CTRB1
DOVITINIB	3	MARK4, SRPK2
LESTAURTINIB	3	MARK4, SRPK2, TGFBR1
RUBOXISTAURIN	3	SRPK2
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
SURAMIN	3	TIMP3
CURCUMIN	3	TYR
RESVERATROL	3	TYR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	9	RORB, CFB, SRPK2, TGFBR1, TYR, VEGFA, MARK4, ACAD10, CTRB1
B	Phased (≥1) drug, not yet approved	6	TIMP3, TRPC4, CD63, CETP, LSM14A, CTRB2
C	Druggable family + PDB, no drug	9	CFHR1, TNXB, C2, C3, C9, TRPM3, PILRB, PILRA, ACKR3
D	Druggable family + AlphaFold only, no drug	11	ADAMTS9, SLC16A8, CFHR4, CFHR3, NMRK2, KCNT2, ASPM, SDK1, CNTN4, CNTN6 (+1 more)
E	Difficult family or no structure, no drug	40	RLBP1, RREB1, SKIC2, WHR1, SYN3, TNFRSF10A, UQCRFS1, VTN, CDH22, ATP6V0D1 (+30 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CFHR1	0	CFB
C3	15	CFB
CFHR3	0	CFB
CFHR5	0	CFB
ACKR3	102	—
RLBP1	0	—
RREB1	0	—
SKIC2	0	—
WHR1	36	—
SYN3	0	—
TNFRSF10A	3	—
TNXB	0	—
C2	4	—
UQCRFS1	0	—
VTN	1	—
ADAMTS9	0	—
CDH22	0	—
C9	1	—
ATP6V0D1	0	—
NELFE	0	—
PLEKHA1	1	—
SNX7	0	—
CIMIP1	0	—
SLC16A8	2	—
CD34	0	—
PKNOX2	0	—
POSTN	0	—
CFHR4	0	—
DPF3	0	—
NMRK2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 679.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	388
PHASE2	79
PHASE3	55
PHASE4	50
PHASE1/PHASE2	42
PHASE1	42
PHASE2/PHASE3	15
EARLY_PHASE1	8

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06683950	PHASE4	RECRUITING	Switching to Aflibercept 8mg in Patients Showing Limited Response to Previous Treatment
NCT06970665	PHASE4	RECRUITING	A Study About the Safety of ASP3021 Eye Injections and if They Help People in Japan With Vision Loss From Age-related Macular Degeneration
NCT07187804	PHASE4	NOT_YET_RECRUITING	Long Term Efficacy of Faricimab Using a Treat and Extend Regimen for Type 3 Macular Neovascularization
NCT07403825	PHASE4	RECRUITING	Efficacy of Faricimab in Patients With Subretinal Hyper-reflective Material
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
NCT00134667	PHASE4	TERMINATED	Macugen (Pegaptanib Sodium) Alone, Versus Macugen in Combination With PDT (Photodynamic Therapy) With Visudyne (Verteporfin) in Patients With Age-Related Macular Degeneration (AMD)
NCT00135837	PHASE4	COMPLETED	Photodynamic Therapy in Occult-Only Lesions (POOL)
NCT00327470	PHASE4	TERMINATED	An Open Label Trial to Investigate Macugen for the Preservation of Visual Function in Subjects With Neovascular AMD
NCT00331435	PHASE4	COMPLETED	PDT Study for Exudative AMD With PCV
NCT00354445	PHASE4	UNKNOWN	A Clinical Trial to Explore the Safety and Efficacy of Injections of Macugen When Given Every 6 Weeks in Subjects With AMD
NCT00423189	PHASE4	TERMINATED	Lucentis Utilizing Visudyne (LUV Trial) Combination Therapy in the Treatment of Age-Related Macular Degeneration
NCT00478439	PHASE4	TERMINATED	Investigation of Macular Pigment Augmentation on Dark Adaptation
NCT00556348	PHASE4	COMPLETED	Intravitreal Bevacizumab for Choridal Neovascularization Secondary to Age-Related Macular Degeneration
NCT00680498	PHASE4	COMPLETED	Combination Lucentis and Ocular Photodynamic Therapy With Visudyne, With Evaluation-based Retreatment
NCT00805649	PHASE4	COMPLETED	Combined Therapy in Age-Related Macular Degeneration (ARMD)
NCT01148511	PHASE4	COMPLETED	Comparison of Safety, Effectiveness and Quality of Life Outcomes Between Labeled Versus Treat and Extend Regimen in Turkish Patients With Choroidal Neovascularisation Due to Age-related Macular Degeneration (AMD)
NCT01165801	PHASE4	COMPLETED	Size Progression of Macular Degeneration After Cataract Surgery
NCT01319188	PHASE4	TERMINATED	Ranibizumab and the Risk of Arterial Thromboembolic Events
NCT01453920	PHASE4	COMPLETED	Wet AMD Recurrence Rate in Patients Stable on Three Month Ranibizumab Dosing
NCT01464723	PHASE4	COMPLETED	Study EvAluating Genotypes While Using Lucentis 2
NCT01495221	PHASE4	COMPLETED	To Evaluate The Role of Intravitreal Aflibercept Injection (2.0 mg) in the Management of Previously Treated Patients With Exudative AMD
NCT01543568	PHASE4	COMPLETED	Study for Recalcitrant Age Related Macular Degeneration
NCT01573572	PHASE4	COMPLETED	Extension Study to Gather Data on Effect of Macugen on the Corneal Endothelium
NCT01657669	PHASE4	UNKNOWN	Short-term Clinical Effects of Intravitreal Aflibercept Injection 2.0mg as a Predictor of Long-term Results
NCT01670162	PHASE4	UNKNOWN	On-label tReatment With Intravitreal Aflibercept injectiOn for Patients With Persistent Pigment epitheliaL Detachments in Neovascular Age Related Macular Degeneration (AMD)
NCT01824225	PHASE4	COMPLETED	Study of PRN and Every 2months Intravitreal Aflibercept for Age Related Macular Degeneration
NCT01846273	PHASE4	COMPLETED	Visual Outcome in Patients With Symptomatic Macular Polypoidal Choroidal Vasculopathy (PCV) Treated With Either Ranibizumab as Monotherapy or Combined With Verteporfin Photodynamic Therapy (vPDT)
NCT01943396	PHASE4	UNKNOWN	Treatment of AMD With Rheohemapheresis /RHF/
NCT02002377	PHASE4	TERMINATED	Intravitreal Aflibercept in Wet Age Related Macular Degeneration Patients With an Incomplete Response to Routine Ranibizumab Injections
NCT02130024	PHASE4	COMPLETED	A Comparison of Ranibizumab and Aflibercept for the Development of Geographic Atrophy in (Wet) AMD Patients
NCT02140411	PHASE4	COMPLETED	Efficacy and Safety of Lucentis® (Ranibizumab Intravitreal Injections) in Chilean Patients With Diabetic Macular Edema.
NCT02441816	PHASE4	COMPLETED	VITAL - Individualising Therapy for Neovascular AMD With Aflibercept
NCT02577107	PHASE4	COMPLETED	Head to Head Study of Anti-VEGF Treatment.
NCT02681783	PHASE4	UNKNOWN	PRedictive Factors and Changes From Treatment in iPCV Versus CSR Versus nAMD With afLibercept
NCT02802657	PHASE4	UNKNOWN	Efficacy and Safety of Treat-and-Extend Regimen Versus Pro Re Nata of Conbercept in Age-related Macular Degeneration
NCT02864472	PHASE4	UNKNOWN	Comparison of PDT Combination With Ranibizumab vs. Ranibizumab Monotherapy in Persistent PCV With Initial Loading Dose
NCT03056079	PHASE4	UNKNOWN	Cytokine and Visual Outcome Variations in Eyes Receiving Aflibercept
NCT03056092	PHASE4	UNKNOWN	Cytokine and Visual Outcome Variations in Eyes Receiving Ranibizumab
NCT03117634	PHASE4	COMPLETED	An Open Label-study to Compare the Efficacy of Aflibercept Monotherapy for Polypoidal Choroidal Vasculopathy
NCT03205202	PHASE4	UNKNOWN	Cataract and AMD in a Trial of a Multivitamin and Cocoa Extract

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RANIBIZUMAB	4	86
AFLIBERCEPT	4	11
BROLUCIZUMAB	4	8
FARICIMAB	4	5
VERTEPORFIN	4	5
BRIMONIDINE	4	4
BEVACIZUMAB	4	3
PROPARACAINE	4	3
PROPRANOLOL	4	3
FLUOCINOLONE ACETONIDE	4	2
PEGCETACOPLAN	4	2
VITAMIN A PALMITATE	4	2
ACETAZOLAMIDE	4	1
ACYCLOVIR	4	1
ARTENIMOL	4	1
BETAMETHASONE	4	1
BROMFENAC	4	1
CHLORHEXIDINE	4	1
COCAINE	4	1
DACLIZUMAB	4	1
DEXAMETHASONE	4	1
DISULFIRAM	4	1
ECULIZUMAB	4	1
EFALIZUMAB	4	1
FLUORESCEIN	4	1
HYDRALAZINE HYDROCHLORIDE	4	1
HYPOCHLOROUS ACID	4	1
IPTACOPAN	4	1
LIDOCAINE HYDROCHLORIDE	4	1
MOXIFLOXACIN	4	1