Macular degeneration

disease

On this page

Also known as macula lutea retinal degenerationmacula retinal degenerationretinal degeneration of macula lutea

Summary

Macular degeneration (MONDO:0003004) is a disease (an umbrella term covering 9 Mondo subtypes) with 10 cohort genes (84 GWAS associations across 30 studies) and 285 clinical trials. Top therapeutic interventions include ranibizumab, verteporfin, and pegaptanib sodium.

At a glance

Umbrella term: 9 Mondo subtypes
Cohort genes: 10
GWAS associations: 84
ClinVar variants: 76
Clinical trials: 285

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	macular degeneration
Mondo ID	MONDO:0003004
EFO	EFO:0009606
MeSH	D008268
DOID	DOID:4448
NCIT	C123330
SNOMED CT	422338006
UMLS	C0024437
MedGen	7434
Anatomy (UBERON)	UBERON:0000053
Is cancer (heuristic)	no

Also known as: macula lutea retinal degeneration · macula retinal degeneration · retinal degeneration of macula lutea

Data availability: 76 ClinVar variants · 84 GWAS associations (30 studies) · 1 cell line.

Disease family

An umbrella term covering 9 Mondo subtypes.

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

Subtypes (9): vitelliform macular dystrophy, degeneration of macula and posterior pole, macular retinal edema, autosomal recessive bestrophinopathy, occult macular dystrophy, macular degeneration, early-onset, Stargardt disease, patterned macular dystrophy, isolated macular dystrophy

Genetics & variants

GWAS landscape

84 GWAS associations across 30 studies. Top hits map to 20 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1329424	1e-323	CFH	T	0.44
rs3043084	1e-323	KCNT2 - CFH	A	0.59
chr10:124202126	1e-323		T	0.48
rs61871744	1e-323	HTRA1-AS1	T	0.8
rs579745	6e-312	CFH	A	0.42
chr1:196670757	5e-240		C	0.56
rs36212732	6e-239	ARMS2, HTRA1-AS1	A	0.44
rs488380	1e-236	CFH	C	0.53
rs10490924	7e-218	HTRA1-AS1, ARMS2	G	0.38
rs429608	4e-110	SKIC2	G	0.33
rs2230199	2e-94	C3	G	0.22
rs1129038	1e-52	HERC2	C	0.17
rs3816117	1e-32	CETP	T	0.11
chr1:196671981	3e-32		T	0.52
rs4711751	5e-32	LINC02537 - LINC01512	T	0.1
rs141853578	9e-27	CFI	C	1.18
rs56156922	1e-26	HERPUD1 - CETP	T	0.11
rs34882957	2e-25	C9	G	0.44
rs11200630	2e-23	HTRA1-AS1	T	0.44
rs429358	3e-20	APOE	T	0.12
chr1:196665208	2e-18		A	0.69
rs485741	2e-17	RN7SKP146 - CLUL1	A	0.11
rs3138141	3e-17	RDH5	C	0.1
chr1:207991209	7e-17		C	0.1
chr10:124221276	7e-17		G	0.66
rs11200633	9e-17	HTRA1-AS1	?
rs56075814	2e-16	MIR29B2CHG	T	0.1
chr16:56993886	2e-15		A	0.09
chr6:116446576	2e-15		A	0.07
rs11628653	3e-15	RAD51B	G	0.08

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475851	Verma A	2024	27,144	412,580	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475386	Verma A	2024	17,289	298,379	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475387	Verma A	2024	7,820	307,848	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475852	Verma A	2024	7,388	440,688	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90079434	Backman JD	2021	4,185	33,613	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083420	Backman JD	2021	4,185	33,613	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90044338	Jiang L	2021	3,493	144,486	A generalized linear mixed model association tool for biobank-scale data.
GCST90476820	Verma A	2024	1,691	53,814	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479648	Verma A	2024	1,691	53,814	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475850	Verma A	2024	1,519	57,488	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	7
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	37

MAF distribution

Bucket	Variants
common (>=0.05)	41
low_freq (0.01-0.05)	2
rare (<0.01)	3
unknown	0

Functional consequences

Consequence	Count
intron_variant	20
unknown	11
missense_variant	7
intergenic_variant	5
3_prime_UTR_variant	2
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1329424	1	196677046	T>A,C,G	0.382	intron_variant	CFH	1e-323	Tier 4: intronic/intergenic
rs3043084	1	196631261	A>G	0.27	intergenic_variant	KCNT2 - CFH	1e-323	Tier 4: intronic/intergenic
chr10:124202126				0.154			1e-323	Tier 4: intronic/intergenic
rs61871744	10	122444271	T>A,C	0.204	intron_variant	HTRA1-AS1	1e-323	Tier 4: intronic/intergenic
rs579745	1	196695446	A>C,T	0.355	intron_variant	CFH	6e-312	Tier 4: intronic/intergenic
chr1:196670757				0.391			5e-240	Tier 4: intronic/intergenic
rs36212732	10	122455682	A>G	0.211	intron_variant	ARMS2, HTRA1-AS1	6e-239	Tier 4: intronic/intergenic
rs488380	1	196695375	C>A,G,T	0.356	intron_variant	CFH	1e-236	Tier 4: intronic/intergenic
rs10490924	10	122454932	G>C,T	0.22	missense_variant	HTRA1-AS1, ARMS2	7e-218	Tier 1: coding
rs429608	6	31962685	G>A	0.161	intron_variant	SKIC2	4e-110	Tier 4: intronic/intergenic
rs2230199	19	6718376	G>A,C,T	0.209	missense_variant	C3	2e-94	Tier 1: coding
rs1129038	15	28111713	C>A,G,T	0.253	3_prime_UTR_variant	HERC2	1e-52	Tier 2: splice/UTR
rs3816117	16	56962246	T>A,C,G	0.483	intron_variant	CETP	1e-32	Tier 4: intronic/intergenic
chr1:196671981				0.239			3e-32	Tier 4: intronic/intergenic
rs4711751	6	43860845	T>A,C	0.497	intron_variant	LINC02537 - LINC01512	5e-32	Tier 4: intronic/intergenic
rs141853578	4	109764664	C>T	0.001	missense_variant	CFI	9e-27	Tier 1: coding
rs56156922	16	56953457	T>C	0.281	intergenic_variant	HERPUD1 - CETP	1e-26	Tier 4: intronic/intergenic
rs34882957	5	39331792	G>A	0.009	missense_variant	C9	2e-25	Tier 1: coding
rs11200630	10	122450168	T>C,G	0.241	intron_variant	HTRA1-AS1	2e-23	Tier 4: intronic/intergenic
rs429358	19	44908684	T>C	0.14	missense_variant	APOE	3e-20	Tier 1: coding
chr1:196665208				0.255			2e-18	Tier 4: intronic/intergenic
rs485741	18	594505	A>C,G,T	0.156	intergenic_variant	RN7SKP146 - CLUL1	2e-17	Tier 4: intronic/intergenic
rs3138141	12	55721994	C>A,G,T	0.215	3_prime_UTR_variant	RDH5	3e-17	Tier 2: splice/UTR
chr1:207991209				0.208			7e-17	Tier 4: intronic/intergenic
chr10:124221276				0.241			7e-17	Tier 4: intronic/intergenic
rs11200633	10	122452080	C>A,T	0.05	intron_variant	HTRA1-AS1	9e-17	Tier 4: intronic/intergenic
rs56075814	1	207802604	T>C	0.204	intron_variant	MIR29B2CHG	2e-16	Tier 4: intronic/intergenic
chr16:56993886				0.319			2e-15	Tier 4: intronic/intergenic
chr6:116446576				0.389			2e-15	Tier 4: intronic/intergenic
rs11628653	14	68352259	G>A,C,T	0.425	intron_variant	RAD51B	3e-15	Tier 4: intronic/intergenic

ClinVar germline variants

76 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 25 conflicting classifications of pathogenicity, 11 benign/likely benign, 5 benign, 4 pathogenic/likely pathogenic, 2 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
373916	NM_000350.3(ABCA4):c.688T>A (p.Cys230Ser)	ABCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
92871	NM_000350.3(ABCA4):c.67-2A>G	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
99460	NM_000350.3(ABCA4):c.6445C>T (p.Arg2149Ter)	ABCA4	Pathogenic	reviewed by expert panel
225010	NM_024685.4(BBS10):c.145C>T (p.Arg49Trp)	BBS10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9481	NM_001298.3(CNGA3):c.829C>T (p.Arg277Cys)	CNGA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
98671	NM_000322.5(PRPH2):c.469G>A (p.Asp157Asn)	PRPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
908037	NM_000063.6(C2):c.1577A>G (p.Lys526Arg)	C2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356269	NM_001710.6(CFB):c.291G>A (p.Glu97=)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356270	NM_001710.6(CFB):c.321C>T (p.His107=)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356275	NM_001710.6(CFB):c.604C>T (p.Arg202Trp)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356278	NM_001710.6(CFB):c.720G>A (p.Glu240=)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356279	NM_001710.6(CFB):c.724A>C (p.Ile242Leu)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356283	NM_001710.6(CFB):c.1037-10C>T	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356288	NM_001710.6(CFB):c.1407C>G (p.Ile469Met)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356291	NM_001710.6(CFB):c.1593T>C (p.Asp531=)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356298	NM_001710.6(CFB):c.*47C>T	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903818	NM_001710.6(CFB):c.1290C>T (p.Val430=)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903888	NM_001710.6(CFB):c.1956+10G>A	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906097	NM_001710.6(CFB):c.274A>T (p.Thr92Ser)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906166	NM_001710.6(CFB):c.784G>A (p.Val262Ile)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907233	NM_001710.6(CFB):c.1838C>T (p.Thr613Ile)	CFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2945	NM_012418.4(FSCN2):c.72del (p.Thr25fs)	FSCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299046	NM_002775.5(HTRA1):c.245C>G (p.Pro82Arg)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299048	NM_002775.5(HTRA1):c.472+6C>A	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299050	NM_002775.5(HTRA1):c.843C>T (p.Ala281=)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
731317	NM_002775.5(HTRA1):c.1094C>T (p.Thr365Met)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
739343	NM_002775.5(HTRA1):c.1350C>T (p.Asp450=)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
871446	NM_002775.5(HTRA1):c.34C>T (p.Leu12=)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877206	NM_002775.5(HTRA1):c.12G>T (p.Pro4=)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878249	NM_002775.5(HTRA1):c.176G>C (p.Arg59Pro)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · 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
C2	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
RAX2	Orphanet:1872	Cone rod dystrophy
CNGA3	Orphanet:1872	Cone rod dystrophy
CNGA3	Orphanet:49382	Achromatopsia
TOPORS	Orphanet:2754	Orofaciodigital syndrome type 6
TOPORS	Orphanet:791	Retinitis pigmentosa
BBS10	Orphanet:110	Bardet-Biedl syndrome
ABCA4	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:827	Stargardt disease
FSCN2	Orphanet:791	Retinitis pigmentosa
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
HTRA1	Orphanet:482077	HTRA1-related autosomal dominant cerebral small vessel disease
PRPH2	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:227796	Fundus albipunctatus
PRPH2	Orphanet:52427	Retinitis punctata albescens
PRPH2	Orphanet:75377	Central areolar choroidal dystrophy
PRPH2	Orphanet:791	Retinitis pigmentosa
PRPH2	Orphanet:827	Stargardt disease
PRPH2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PRPH2	Orphanet:99003	Multifocal pattern dystrophy simulating fundus flavimaculatus

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CFB	HGNC:1037	ENSG00000243649	P00751	Complement factor B	clinvar
C2	HGNC:1248	ENSG00000166278	P06681	Complement C2	clinvar
RAX2	HGNC:18286	ENSG00000173976	Q96IS3	Retina and anterior neural fold homeobox protein 2	clinvar
CNGA3	HGNC:2150	ENSG00000144191	Q16281	Cyclic nucleotide-gated channel alpha-3	clinvar
TOPORS	HGNC:21653	ENSG00000197579	Q9NS56	E3 ubiquitin-protein ligase Topors	clinvar
BBS10	HGNC:26291	ENSG00000179941	Q8TAM1	BBSome complex assembly protein BBS10	clinvar
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	clinvar
FSCN2	HGNC:3960	ENSG00000186765	O14926	Fascin-2	clinvar
HTRA1	HGNC:9476	ENSG00000166033	Q92743	Serine protease HTRA1	clinvar
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
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…
RAX2	Retina and anterior neural fold homeobox protein 2	May be involved in modulating the expression of photoreceptor specific genes.
CNGA3	Cyclic nucleotide-gated channel alpha-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
TOPORS	E3 ubiquitin-protein ligase Topors	Functions as an E3 ubiquitin-protein ligase and as an E3 SUMO1-protein ligase.
BBS10	BBSome complex assembly protein BBS10	Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis.
ABCA4	Retinal-specific phospholipid-transporting ATPase ABCA4	Flippase that catalyzes in an ATP-dependent manner the transport of retinal-phosphatidylethanolamine conjugates like 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leafl…
FSCN2	Fascin-2	Acts as an actin bundling protein.
HTRA1	Serine protease HTRA1	Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin.
PRPH2	Peripherin-2	Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.5

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
Protease	3	11.0×	0.011
Ion channel	1	11.2×	0.202
Transporter	1	7.8×	0.202
Transcription factor	2	1.6×	0.433
Other/Unknown	3	0.5×	0.976

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CFB	Protease	yes	3.4.21.47	Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
C2	Protease	yes		Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
RAX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
CNGA3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
TOPORS	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
BBS10	Other/Unknown	no		Cpn60/GroEL/TCP-1, GroEL-like_apical_dom_sf, TCP-1-like_intermed_sf
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR
FSCN2	Other/Unknown	no		Actin-crosslinking, Fascin, Fascin-like_dom
HTRA1	Protease	yes	3.4.21.107	IGFBP-like, PDZ, Peptidase_S1C
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
tendon of biceps brachii	2
male germ line stem cell (sensu Vertebrata) in testis	2
ventricular zone	2
calcaneal tendon	2
gall bladder	1
placenta	1
buccal mucosa cell	1
vena cava	1
ganglionic eminence	1
secondary oocyte	1
sperm	1
endothelial cell	1
pigmented layer of retina	1
primordial germ cell in gonad	1
frontal pole	1
middle frontal gyrus	1
paraflocculus	1
metanephric glomerulus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CFB	134	broad	marker	right lobe of liver, liver, gall bladder
C2	138	ubiquitous	marker	liver, right lobe of liver, placenta
RAX2	39	tissue_specific	marker	tendon of biceps brachii, buccal mucosa cell, vena cava
CNGA3	110	tissue_specific	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence
TOPORS	285	ubiquitous	marker	secondary oocyte, calcaneal tendon, sperm
BBS10	253	ubiquitous	yes	calcaneal tendon, endothelial cell, ventricular zone
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
FSCN2	148	tissue_specific	yes	frontal pole, paraflocculus, middle frontal gyrus
HTRA1	287	ubiquitous	marker	tendon of biceps brachii, renal glomerulus, metanephric glomerulus
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BBS10	3,224
HTRA1	2,843
CFB	1,997
TOPORS	1,552
ABCA4	1,532
PRPH2	1,234
CNGA3	1,166
C2	937
FSCN2	805
RAX2	754

Intra-cohort edges

A	B	Sources
ABCA4	C2	string_interaction
ABCA4	PRPH2	string_interaction
ABCA4	RAX2	string_interaction
C2	RAX2	string_interaction
FSCN2	TOPORS	string_interaction
PRPH2	TOPORS	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFB	P00751	26
HTRA1	Q92743	18
C2	P06681	14
CNGA3	Q16281	10
ABCA4	P78363	8
PRPH2	P23942	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FSCN2	O14926	93.79
RAX2	Q96IS3	71.72
BBS10	Q8TAM1	71.26
TOPORS	Q9NS56	49.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 10 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of C3 and C5	2	362.5×	3e-04	CFB, C2
Regulation of Complement cascade	2	66.6×	0.004	CFB, C2
Defective visual phototransduction due to ABCA4 loss of function	1	1631.4×	0.005	ABCA4
Retinoid cycle disease events	1	407.9×	0.010	ABCA4
Diseases associated with visual transduction	1	407.9×	0.010	ABCA4
Diseases of the neuronal system	1	407.9×	0.010	ABCA4
Alternative complement activation	1	326.3×	0.010	CFB
SUMOylation of immune response proteins	1	135.9×	0.022	TOPORS
Initial triggering of complement	1	85.9×	0.031	C2
The canonical retinoid cycle in rods (twilight vision)	1	74.2×	0.031	ABCA4
BBSome-mediated cargo-targeting to cilium	1	70.9×	0.031	BBS10
SUMOylation of SUMOylation proteins	1	46.6×	0.043	TOPORS
Visual phototransduction	1	37.1×	0.046	ABCA4
Cargo trafficking to the periciliary membrane	1	35.5×	0.046	BBS10
SUMOylation of transcription cofactors	1	34.7×	0.046	TOPORS
Sensory processing of sound by outer hair cells of the cochlea	1	29.1×	0.051	FSCN2
Sensory processing of sound by inner hair cells of the cochlea	1	23.3×	0.059	FSCN2
ABC-family protein mediated transport	1	17.4×	0.073	ABCA4
Degradation of the extracellular matrix	1	16.8×	0.073	HTRA1
Cilium Assembly	1	15.5×	0.075	BBS10
Sensory Perception	1	13.6×	0.081	ABCA4
Organelle biogenesis and maintenance	1	9.4×	0.111	BBS10
Transport of small molecules	1	3.6×	0.258	ABCA4
Disease	1	1.9×	0.427	ABCA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
visual perception	6	47.7×	6e-08	RAX2, CNGA3, BBS10, ABCA4, FSCN2, PRPH2
photoreceptor cell outer segment organization	2	210.7×	0.001	TOPORS, PRPH2
complement activation	2	124.8×	0.003	CFB, C2
photoreceptor cell maintenance	2	71.7×	0.006	BBS10, ABCA4
response to low light intensity stimulus	1	1685.2×	0.008	PRPH2
retina development in camera-type eye	2	51.1×	0.008	CNGA3, PRPH2
inorganic cation import across plasma membrane	1	842.6×	0.011	CNGA3
response to bacterium	2	38.7×	0.011	CFB, C2
phospholipid transfer to membrane	1	561.7×	0.013	ABCA4
retinal cone cell differentiation	1	561.7×	0.013	BBS10
cone retinal bipolar cell differentiation	1	421.3×	0.016	BBS10
proteolysis	3	10.3×	0.016	CFB, C2, HTRA1
chorionic trophoblast cell differentiation	1	280.9×	0.021	HTRA1
positive regulation of apoptotic cell clearance	1	240.7×	0.022	C2
response to thyroid hormone	1	210.7×	0.024	C2
retinal rod cell differentiation	1	187.2×	0.025	BBS10
response to magnesium ion	1	140.4×	0.029	CNGA3
phototransduction, visible light	1	129.6×	0.029	ABCA4
programmed cell death	1	129.6×	0.029	HTRA1
complement activation, GZMK pathway	1	129.6×	0.029	C2
maintenance of protein location in nucleus	1	112.3×	0.032	TOPORS
protein heterooligomerization	1	105.3×	0.032	PRPH2
complement activation, alternative pathway	1	99.1×	0.033	CFB
retinal metabolic process	1	93.6×	0.033	ABCA4
response to light stimulus	1	88.7×	0.034	BBS10
eye photoreceptor cell development	1	84.3×	0.034	FSCN2
monoatomic cation transport	1	76.6×	0.036	CNGA3
regulation of protein-containing complex assembly	1	73.3×	0.036	BBS10
chaperone-mediated protein complex assembly	1	70.2×	0.036	BBS10
retina layer formation	1	64.8×	0.036	TOPORS

Therapeutics

Drugs indicated for this disease

1 approved, 16 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)
Aflibercept	Phase 3 (in late-stage trials)
Alprostadil	Phase 3 (in late-stage trials)
Anecortave Acetate	Phase 3 (in late-stage trials)
Ascorbic Acid	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Beta Carotene	Phase 3 (in late-stage trials)
Bevacizumab	Phase 3 (in late-stage trials)
Bevasiranib	Phase 3 (in late-stage trials)
Celecoxib	Phase 3 (in late-stage trials)
Faricimab	Phase 3 (in late-stage trials)
Pegaptanib 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)
Vitamin E	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Albumin Human, Avacincaptad Pegol Sodium, Ciliary Neurotrophic Factor, Fluocinolone Acetonide, Glatiramer Acetate, Human Immunoglobulin G, Mecamylamine, Ocriplasmin, Pazopanib, Regorafenib, Sodium Chloride.

Drug target analysis

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

Druggability breadth: 3 of 10 evidence-associated genes (30%) 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
CFB	IPTACOPAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CFB	1	4
C2	0	0
RAX2	0	0
CNGA3	0	0
TOPORS	0	0
BBS10	0	0
ABCA4	0	0
FSCN2	0	0
HTRA1	0	0
PRPH2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IPTACOPAN	4	CFB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CFB	33	Binding:33
HTRA1	28	Binding:28
C2	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFB	3.4.21.47	alternative-complement-pathway C3/C5 convertase
HTRA1	3.4.21.107, 3.4.21.108	peptidase Do, HtrA2 peptidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
IPTACOPAN	4	CFB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CFB
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	4	C2, CNGA3, ABCA4, HTRA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	RAX2, TOPORS, BBS10, FSCN2, PRPH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C2	4	—
RAX2	0	—
CNGA3	0	—
TOPORS	0	—
BBS10	0	—
ABCA4	0	—
FSCN2	0	—
HTRA1	28	—
PRPH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 285.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	117
PHASE2	51
PHASE3	44
PHASE1	35
PHASE1/PHASE2	17
PHASE4	12
PHASE2/PHASE3	7
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07367282	PHASE4	NOT_YET_RECRUITING	Evaluate the Efficacy of Faricimab in Patients With Neovascular Age-related Macular Degeneration
NCT00312351	PHASE4	TERMINATED	A Clinical Trial to Explore the Safety and Efficacy of Three Different Doses of Pegaptanib Sodium in Patients With Wet Age-Related Macular Degeneration (AMD)
NCT00324116	PHASE4	COMPLETED	Evaluation Of Safety And Efficacy Of 0.3 Mg/Eye Macugen In Patients With Small Age-Related Macular Degeneration Lesions
NCT00327470	PHASE4	TERMINATED	An Open Label Trial to Investigate Macugen for the Preservation of Visual Function in Subjects With Neovascular AMD
NCT00533520	PHASE4	COMPLETED	Evaluation of Dosing Interval of Higher Doses of Ranibizumab
NCT00813891	PHASE4	UNKNOWN	Efficacy of Ranibizumab in Combination With Photodynamic Therapy for Wet Age-Related Macular Degeneration
NCT01006538	PHASE4	COMPLETED	Macular EpiRetinal Brachytherapy Versus Lucentis® Only Treatment (MERLOT)
NCT01213667	PHASE4	UNKNOWN	Genetics in Non-response to Anti-VEGF Treatment in Exudative AMD
NCT01831947	PHASE4	COMPLETED	Efficacy Study of Ranibizumab on Patients With Age-related Macular Degeneration.
NCT02581891	PHASE4	COMPLETED	Managing Neovascular (Known as Wet) Age-related Macular Degeneration Over 2 Years Using Different Treatment Schedules of 2 mg Intravitreal Aflibercept Injected in the Eye
NCT02689518	PHASE4	COMPLETED	EAGLE: Evaluating Genotypes Using Intravitreal Aflibercept Injection
NCT03804099	PHASE4	COMPLETED	Effect Aflibercept on Ocular Perfusion
NCT06305416	PHASE3	RECRUITING	A Efficacy and Safety Study of Ranibizumab 10mg/ml Injection (Incepta) in Patients With Diabetic Macular Edema
NCT07440225	PHASE2/PHASE3	RECRUITING	A Clinical Trial of EYE201/MK-8748 in People With Macular Degeneration (MK-8748-002)
NCT07496567	PHASE2/PHASE3	RECRUITING	A Clinical Trial of EYE201/MK-8748 in People With Macular Degeneration (MK-8748-003)
NCT00000145	PHASE3	COMPLETED	Age-Related Eye Disease Study (AREDS)
NCT00000150	PHASE3	COMPLETED	Submacular Surgery Trials (SST)
NCT00000152	PHASE3	UNKNOWN	Randomized Trial of Beta-Carotene and Macular Degeneration
NCT00000158	PHASE3	UNKNOWN	Macular Photocoagulation Study (MPS)
NCT00000161	PHASE3	UNKNOWN	Randomized Trials of Vitamin Supplements and Eye Disease
NCT00000162	PHASE3	COMPLETED	Branch Vein Occlusion Study
NCT00000167	PHASE3	COMPLETED	Complications of Age-Related Macular Degeneration Prevention Trial
NCT00021736	PHASE2/PHASE3	COMPLETED	Phase II/III Study of Anti-VEGF in Neovascular AMD
NCT00041483	PHASE3	COMPLETED	Phase 3 Study to Evaluate Anecortave Acetate vs. Visudyne for the Treatment of the Wet Form of AMD
NCT00042211	PHASE3	COMPLETED	Preventing Depression in Patients With Macular Degeneration
NCT00050479	PHASE3	COMPLETED	Laser and Medical Treatment of Diabetic Macular Edema
NCT00051129	PHASE3	COMPLETED	Anecortave Acetate in Subfoveal Choroidal Neovascularization (CNV) Due to Wet Age-Related Macular Degeneration (AMD)
NCT00056836	PHASE3	COMPLETED	A Study to Evaluate rhuFab V2 in Subjects With Minimally Classic or Occult Subfoveal Neovascular Macular Degeneration
NCT00058994	PHASE3	COMPLETED	An Evaluation of Safety and Efficacy of Anecortave Acetate Versus Placebo in Patients With Subfoveal CNV Due to Exudative AMD
NCT00061594	PHASE3	COMPLETED	A Study to Compare rhuFab V2 With Verteporfin Photodynamic in Treating Subfoveal Neovascular Macular Degeneration
NCT00065728	PHASE3	TERMINATED	Open-Label Posterior Juxtascleral Injections of Anecortave Acetate 15mg Dose for Long Term Use in Patients With AMD
NCT00078221	PHASE3	UNKNOWN	Rheopheresis Blood Filtration Study for the Treatment of Dry Age-Related Macular Degeneration (AMD)
NCT00090623	PHASE3	COMPLETED	A Study of rhuFab V2 (Ranibizumab) in Subjects With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (AMD)
NCT00095433	PHASE3	COMPLETED	Extension Study of rhuFab V2 in Subjects With Neovascular Age-Related Macular Degeneration (AMD)
NCT00100009	PHASE3	COMPLETED	Triamcinolone Acetonide Plus Laser Therapy to Treat Age-Related Macular Degeneration
NCT00121407	PHASE3	COMPLETED	Visudyne® in Occult (VIO)
NCT00150202	PHASE3	COMPLETED	Clinical Study Of EYE001 For Wet-Type AMD (Age-Related Macular Degeneration)
NCT00157976	PHASE3	UNKNOWN	Double-Masked Study of Photrex (Rostaporfin) Photodynamic Therapy in the Treatment of Age-Related Macular Degeneration
NCT00242580	PHASE3	COMPLETED	A Safety and Efficacy Study Comparing the Combination Treatments of Verteporfin Therapy Plus One of Two Different Doses of Intravitreal Triamcinolone Acetonide and the Verteporfin Therapy Plus Intravitreal Pegaptanib
NCT00299507	PHASE3	COMPLETED	Anecortave Acetate in Patients With Exudative Age-related Macular Degeneration (AMD)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RANIBIZUMAB	4	39
VERTEPORFIN	4	8
PEGAPTANIB SODIUM	4	6
AFLIBERCEPT	4	5
BRIMONIDINE	4	4
MECAMYLAMINE	4	3
BETA CAROTENE	4	2
FLUOCINOLONE ACETONIDE	4	2
PAZOPANIB	4	2
TRIAMCINOLONE ACETONIDE	4	2
VITAMIN E	4	2
ACETAZOLAMIDE	4	1
ALBUMIN HUMAN	4	1
ASCORBIC ACID	4	1
CELECOXIB	4	1
DISULFIRAM	4	1
FARICIMAB	4	1
FLUORESCEIN	4	1
OCRIPLASMIN	4	1
PADELIPORFIN POTASSIUM	4	1
PROPARACAINE	4	1
REGORAFENIB	4	1
RITUXIMAB	4	1
TALAPORFIN	4	1
TETRACAINE	4	1
ABICIPAR PEGOL	3	7
ANECORTAVE ACETATE	3	6
BEVASIRANIB	3	3
LUTEIN	3	2
AVACINCAPTAD PEGOL	3	1

Cohort genes: CFB, C2, RAX2, CNGA3, TOPORS, BBS10, ABCA4, FSCN2, HTRA1, PRPH2
Drugs: Ranibizumab, Verteporfin, Pegaptanib, Aflibercept, Brimonidine, Mecamylamine, Beta Carotene, Fluocinolone Acetonide, Pazopanib, Triamcinolone Acetonide, Vitamin E, Acetazolamide, Albumin Human, Ascorbic Acid, Celecoxib, Disulfiram, Faricimab, Fluorescein, Ocriplasmin, Padeliporfin, Proparacaine, Regorafenib, Rituximab, Talaporfin, Tetracaine, Abicipar Pegol, Anecortave Acetate, Bevasiranib, Avacincaptad Pegol