Keratoconus

Summary

Keratoconus (MONDO:0015486) is a disease (an umbrella term covering 11 Mondo subtypes) with 75 cohort genes (78 GWAS associations across 9 studies) and 279 clinical trials. The dominant Reactome pathway is Assembly of collagen fibrils and other multimeric structures (8 cohort genes). Top therapeutic interventions include riboflavin, fluorometholone acetate, and prednisolone acetate.

At a glance

• Umbrella term: 11 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 78
• ClinVar variants: 40
• Clinical trials: 279

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	keratoconus
Mondo ID	MONDO:0015486
MeSH	D007640
OMIM	148300
Orphanet	156071, 2335
DOID	DOID:10126
ICD-10-CM	H18.6
ICD-11	945228622
NCIT	C26806
SNOMED CT	65636009
UMLS	C0022578
MedGen	44015
MedDRA	10023353
Is cancer (heuristic)	no

Also known as: isolated keratoconus · KC · keratoconus · keratoconus (disease) · noninflammatory corneal thining

Data availability: 40 ClinVar variants · 78 GWAS associations (9 studies) · 1 GenCC gene-disease record · 1 HPO phenotype.

Disease family

An umbrella term covering 11 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › corneal disorder › keratoconus

Related subtypes (23): cornea plana, pseudopterygium, corneal deposit, Bowman’s membrane folds or rupture, corneal degeneration, corneal staphyloma, corneal argyrosis, corneal ectasia, keratopathy, keratitis, corneal edema, brittle cornea syndrome, megalocornea, X-linked corneal dermoid, Peters anomaly, pellucid marginal degeneration, corneal dystrophy, sclerocornea, cornea neoplasm, Arnold stickler bourne syndrome, limbal stem cell deficiency, thygeson superficial punctate keratopathy, Terrien marginal degeneration

Subtypes (11): acute hydrops keratoconus, keratoconus, stable condition, keratoconus 1, keratoconus 3, keratoconus 2, keratoconus 4, keratoconus 5, keratoconus 6, keratoconus 8, keratoconus 7, keratoconus 9

Genetics & variants

GWAS landscape

78 GWAS associations across 9 studies. Top hits map to 29 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2721051	6e-35	LINC00598 - FOXO1	T	0.45
rs3118518	2e-28	RXRA - COL5A1	A	0.27
rs7117921	1e-26	PIDD1, RPLP2	T	0.27
rs4894414	1e-26	FNDC3B	T	0.3
rs12912010	2e-26	SMAD3	T	0.31
rs35523808	3e-25	COL12A1	A	0.66
rs840464	2e-20	LOX - ZNF474	T	0.23
rs11117401	4e-20	LINC02182	A	0.24
rs1324175	3e-19	LINC01235 - LINC00583	T	0.24
rs12515400	3e-18	RPL13AP13 - FST	T	0.22
rs375290574	2e-16	RDH8 - C3P1	C	3.69
rs544696584	1e-14	ARHGEF37 - U3	C	3.71
rs12603055	2e-14	KIF1C-AS1, KIF1C	C	0.23
rs188993616	9e-14	MRPS35	C	2.86
rs962307678	5e-13	RN7SKP6 - PRR20A	C	4.16
rs192984922	1e-12	DDX43P2 - VWC2	G	2.97
rs144619021	2e-12	LINC02264 - NDST3	G	3.13
rs17285550	3e-12	KLF5	A	0.18
rs574177860	3e-12	SPRY4-AS1	G	3.41
rs658352	4e-12	EIF3A	T	0.18
rs2143683	4e-12	LINC01695	T	0.18
rs567010138	4e-12	PSD3	C	2.8
rs181856846	4e-12	HSBP1 - MLYCD	G	4
rs575273090	4e-12	IRX1 - LINC02063	C	3.35
rs373192492	5e-12	TMEM213	G	3.63
rs183801341	6e-12	LINC01876	T	3.73
rs532547695	6e-12	HS3ST3B1 - RPS18P12	G	4.04
rs76747345	7e-12	Y_RNA - LINC01684	A	0.55
rs4646785	9e-12	ALDH3A1	T	0.2
rs142493024	9e-12	COL6A1	A	0.76

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90013442	Hardcastle AJ	2021	2,116	24,626	A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.
GCST90837424	Xu L	2024	853	6,248	Association of Novel Loci With Keratoconus Susceptibility in a Chinese Genome-Wide Association Study.
GCST90477661	Verma A	2024	573	450,622	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST009677	McComish BJ	2019	522	0	Association of Genetic Variation With Keratoconus.
GCST90480060	Verma A	2024	367	121,509	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481911	Verma A	2024	367	121,509	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST001274	Burdon KP	2011	319	3,462	Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.
GCST001261	Li X	2011	222	3,324	A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries.
GCST90435979	Zhou W	2018	87	397,761	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	2
Tier 3: regulatory	1
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	27
low_freq (0.01-0.05)	0
rare (<0.01)	21
unknown	2

Functional consequences

Consequence	Count
intron_variant	27
intergenic_variant	17
non_coding_transcript_exon_variant	2
5_prime_UTR_variant	1
missense_variant	1
3_prime_UTR_variant	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2721051	13	40536747	C>G,T	0.05	intron_variant	LINC00598 - FOXO1	6e-35	Tier 4: intronic/intergenic
rs3118518	9	134548237	G>A	0.05	intergenic_variant	RXRA - COL5A1	2e-28	Tier 4: intronic/intergenic
rs7117921	11	800486	C>T	0.05	5_prime_UTR_variant	PIDD1, RPLP2	1e-26	Tier 2: splice/UTR
rs4894414	3	172279709	C>A,T	0.05	intron_variant	FNDC3B	1e-26	Tier 4: intronic/intergenic
rs12912010	15	67174805	G>T	0.05	intron_variant	SMAD3	2e-26	Tier 4: intronic/intergenic
rs35523808	6	75125255	T>A	0.05	missense_variant	COL12A1	3e-25	Tier 1: coding
rs840464	5	122081768	G>T	0.05	intergenic_variant	LOX - ZNF474	2e-20	Tier 4: intronic/intergenic
rs11117401	16	88280846	G>A,C,T	0.05	intron_variant	LINC02182	4e-20	Tier 4: intronic/intergenic
rs1324175	9	13549156	C>A,T	0.05	intron_variant	LINC01235 - LINC00583	3e-19	Tier 4: intronic/intergenic
rs12515400	5	53285349	C>T	0.05	intergenic_variant	RPL13AP13 - FST	3e-18	Tier 4: intronic/intergenic
rs375290574	19	10028881	C>T	0	intergenic_variant	RDH8 - C3P1	2e-16	Tier 4: intronic/intergenic
rs544696584	5	149656432	C>T	0	intron_variant	ARHGEF37 - U3	1e-14	Tier 4: intronic/intergenic
rs12603055	17	5027076	G>A,C,T	0.05	3_prime_UTR_variant	KIF1C-AS1, KIF1C	2e-14	Tier 2: splice/UTR
rs188993616	12	27745673	C>A,T	0.001	intron_variant	MRPS35	9e-14	Tier 4: intronic/intergenic
rs962307678	13	57078141	C>T	0	intron_variant	RN7SKP6 - PRR20A	5e-13	Tier 4: intronic/intergenic
rs192984922	7	49453836	G>A	0.001	intergenic_variant	DDX43P2 - VWC2	1e-12	Tier 4: intronic/intergenic
rs144619021	4	117877256	G>A	0.001	intron_variant	LINC02264 - NDST3	2e-12	Tier 4: intronic/intergenic
rs17285550	13	73070755	A>G	0.05	intron_variant	KLF5	3e-12	Tier 4: intronic/intergenic
rs574177860	5	142409381	G>C	0	intron_variant	SPRY4-AS1	3e-12	Tier 4: intronic/intergenic
rs658352	10	119044276	T>C	0.05	intron_variant	EIF3A	4e-12	Tier 4: intronic/intergenic
rs2143683	21	28158967	T>A,C,G	0.05	intron_variant	LINC01695	4e-12	Tier 4: intronic/intergenic
rs567010138	8	19046420	C>A	0.001	intergenic_variant	PSD3	4e-12	Tier 4: intronic/intergenic
rs181856846	16	83855405	G>C	0	intron_variant	HSBP1 - MLYCD	4e-12	Tier 4: intronic/intergenic
rs575273090	5	3992921	C>T	0.001	intergenic_variant	IRX1 - LINC02063	4e-12	Tier 4: intronic/intergenic
rs373192492	7	138824390	G>A	0.001	intron_variant	TMEM213	5e-12	Tier 4: intronic/intergenic
rs183801341	2	156109824	T>C	0	intron_variant	LINC01876	6e-12	Tier 4: intronic/intergenic
rs532547695	17	14404852	G>A	0	intron_variant	HS3ST3B1 - RPS18P12	6e-12	Tier 4: intronic/intergenic
rs76747345	21	23984911	A>C,G	0.05	non_coding_transcript_exon_variant	Y_RNA - LINC01684	7e-12	Tier 4: intronic/intergenic
rs4646785	17	19748589	C>A,G,T	0.05	regulatory_region_variant	ALDH3A1	9e-12	Tier 3: regulatory
rs142493024	21	45993879	G>A,T		intron_variant	COL6A1	9e-12	Tier 4: intronic/intergenic

ClinVar germline variants

40 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2442791	NM_000691.5(ALDH3A1):c.703G>A (p.Gly235Arg)	ALDH3A1	Likely pathogenic	no assertion criteria provided
2577488	NM_001845.6(COL4A1):c.976G>A (p.Gly326Ser)	COL4A1	Likely pathogenic	no assertion criteria provided
2577487	NM_000393.5(COL5A2):c.4364G>A (p.Gly1455Glu)	COL5A2	Likely pathogenic	no assertion criteria provided
50262	NM_005430.4(WNT1):c.1063G>T (p.Val355Phe)	WNT1	Likely pathogenic	criteria provided, single submitter
225320	NM_000088.4(COL1A1):c.3766G>A (p.Ala1256Thr)	COL1A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
459803	NM_000302.4(PLOD1):c.109G>A (p.Glu37Lys)	PLOD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126928	NM_001367624.2(ZNF469):c.6179C>A (p.Ser2060Tyr)	ZNF469	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2498228	NR_002144.1:n.472_478del		Uncertain significance	no assertion criteria provided
2498236	NC_000004.12:g.69391612A>G		Uncertain significance	no assertion criteria provided
2498237	NR_027420.1:n.875C>T		Uncertain significance	no assertion criteria provided
545133	NM_001395430.1(PAK6):c.1855C>A (p.Pro619Thr)	BUB1B-PAK6	Uncertain significance	no assertion criteria provided
545128	NM_015719.4(COL5A3):c.4204A>C (p.Lys1402Gln)	COL5A3	Uncertain significance	no assertion criteria provided
545131	NM_001395010.1(DAB2IP):c.2759C>T (p.Pro920Leu)	DAB2IP	Uncertain significance	no assertion criteria provided
2445998	NM_001320714.2(DOP1B):c.1227_1228del (p.Gln410fs)	DOP1B	Uncertain significance	no assertion criteria provided
2445997	NM_001039753.4(EML6):c.2528G>T (p.Trp843Leu)	EML6	Uncertain significance	no assertion criteria provided
2445980	NM_000875.5(IGF1R):c.1447G>A (p.Gly483Arg)	IGF1R	Uncertain significance	no assertion criteria provided
2498238	NM_014218.3(KIR2DL1):c.272C>A (p.Thr91Lys)	KIR2DL1	Uncertain significance	no assertion criteria provided
2498239	NM_013289.4(KIR3DL1):c.337G>A (p.Val113Met)	KIR3DL1	Uncertain significance	no assertion criteria provided
2498240	NM_013289.4(KIR3DL1):c.475G>T (p.Gly159Trp)	KIR3DL1	Uncertain significance	no assertion criteria provided
545126	NM_002336.3(LRP6):c.4822C>T (p.Pro1608Ser)	LRP6	Uncertain significance	no assertion criteria provided
2498241	NM_001304359.2(MUC5AC):c.3601C>T (p.Arg1201Trp)	MUC5AC	Uncertain significance	no assertion criteria provided
2498242	NM_001304359.2(MUC5AC):c.5459G>A (p.Arg1820Gln)	MUC5AC	Uncertain significance	no assertion criteria provided
2498243	NM_001304359.2(MUC5AC):c.10301C>T (p.Pro3434Leu)	MUC5AC	Uncertain significance	no assertion criteria provided
2498244	NM_001355281.2(NANOGP8):c.190G>T (p.Asp64Tyr)	NANOGP8	Uncertain significance	no assertion criteria provided
2445999	NM_015175.3(NBEAL2):c.7878+2T>A	NBEAL2	Uncertain significance	no assertion criteria provided
2498229	NM_001351365.2(NBPF19):c.11302C>G (p.Leu3768Val)	NBPF19	Uncertain significance	no assertion criteria provided
545132	NM_001042492.3(NF1):c.5257G>C (p.Val1753Leu)	NF1	Uncertain significance	no assertion criteria provided
545130	NM_173165.3(NFATC3):c.1922G>A (p.Arg641Gln)	NFATC3	Uncertain significance	no assertion criteria provided
545129	NM_001282426.2(PIK3CG):c.711del (p.Asp238fs)	PIK3CG	Uncertain significance	no assertion criteria provided
545127	NM_005605.5(PPP3CC):c.1199T>C (p.Met400Thr)	PPP3CC	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 57 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

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

Gene	HGNC	Evidence routes
COL1A1	COL1A1	GWAS, Orphanet
ZNF469	ZNF469	GWAS, Orphanet
ALDH3A1	ALDH3A1	GWAS

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DOCK9	Limited	Autosomal dominant	keratoconus

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta
ZNF469	Orphanet:90354	Brittle cornea syndrome
RORA	Orphanet:528084	Non-specific syndromic intellectual disability
SGCA	Orphanet:62	Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3
SLC25A15	Orphanet:415	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
TALDO1	Orphanet:101028	Transaldolase deficiency
TFAP2B	Orphanet:46627	Char syndrome
TFAP2B	Orphanet:466729	Familial patent arterial duct
THRB	Orphanet:566243	Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta
TRA	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
TRB	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
WNT1	Orphanet:216812	Osteogenesis imperfecta type 3
WNT1	Orphanet:216820	Osteogenesis imperfecta type 4
WNT1	Orphanet:85193	Idiopathic juvenile osteoporosis
C8G	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency
VANGL1	Orphanet:3027	Caudal regression syndrome
RAB3GAP1	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP1	Orphanet:2510	Micro syndrome
CHRNE	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
SLC25A22	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SLC25A22	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
EPS8L2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
COL12A1	Orphanet:536516	Myopathic Ehlers-Danlos syndrome
COL12A1	Orphanet:610	Bethlem muscular dystrophy
COL12A1	Orphanet:75840	Ullrich congenital muscular dystrophy
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly
COL5A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL5A2	Orphanet:287	Classical Ehlers-Danlos syndrome
COL6A1	Orphanet:610	Bethlem muscular dystrophy
COL6A1	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A1	Orphanet:75840	Ullrich congenital muscular dystrophy

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	55
gwas_and_clinvar	3
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	gwas,clinvar
ZNF469	HGNC:23216	ENSG00000225614	Q96JG9	Zinc finger protein 469	gwas,clinvar
ALDH3A1	HGNC:405	ENSG00000108602	P30838	Aldehyde dehydrogenase, dimeric NADP-preferring	gwas,clinvar
DOCK9	HGNC:14132	ENSG00000088387	Q9BZ29	Dedicator of cytokinesis protein 9	gencc
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gwas
RPLP2	HGNC:10377	ENSG00000177600	P05387	Large ribosomal subunit protein P2	gwas
BHLHE40	HGNC:1046	ENSG00000134107	O14503	Class E basic helix-loop-helix protein 40	gwas
RXRA	HGNC:10477	ENSG00000186350	P19793	Retinoic acid receptor RXR-alpha	gwas
SGCA	HGNC:10805	ENSG00000108823	Q16586	Alpha-sarcoglycan	gwas
SLC25A15	HGNC:10985	ENSG00000102743	Q9Y619	Mitochondrial ornithine transporter 1	gwas
SPAG7	HGNC:11216	ENSG00000091640	O75391	Sperm-associated antigen 7	gwas
TALDO1	HGNC:11559	ENSG00000177156	P37837	Transaldolase	gwas
TFAP2B	HGNC:11743	ENSG00000008196	Q92481	Transcription factor AP-2-beta	gwas
THRB	HGNC:11799	ENSG00000151090	P10828	Thyroid hormone receptor beta	clinvar
TRA	HGNC:12027		P0DSE1	M1-specific T cell receptor alpha chain	clinvar
TRB	HGNC:12155		P0DSE2	M1-specific T cell receptor beta chain	clinvar
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar
WBP4	HGNC:12739	ENSG00000120688	O75554	WW domain-binding protein 4	gwas
WNT1	HGNC:12774	ENSG00000125084	P04628	Proto-oncogene Wnt-1	clinvar
ZFP3	HGNC:12861	ENSG00000180787	Q96NJ6	Zinc finger protein 3 homolog	gwas
DOP1B	HGNC:1291	ENSG00000142197	Q9Y3R5	Protein DOP1B	clinvar
BANP	HGNC:13450	ENSG00000172530	Q8N9N5	Protein BANP	gwas
C8G	HGNC:1354	ENSG00000176919	P07360	Complement component C8 gamma chain	gwas
FBXW5	HGNC:13613	ENSG00000159069	Q969U6	F-box/WD repeat-containing protein 5	gwas
MRPS14	HGNC:14049	ENSG00000120333	O60783	Small ribosomal subunit protein uS14m	gwas
UBXN4	HGNC:14860	ENSG00000144224	Q92575	UBX domain-containing protein 4	gwas
COL5A3	HGNC:14864	ENSG00000080573	P25940	Collagen alpha-3(V) chain	clinvar
VANGL1	HGNC:15512	ENSG00000173218	Q8TAA9	Vang-like protein 1	clinvar
SKAP1	HGNC:15605	ENSG00000141293	Q86WV1	Src kinase-associated phosphoprotein 1	gwas
CCNE2	HGNC:1590	ENSG00000175305	O96020	G1/S-specific cyclin-E2	gwas
ACTL7B	HGNC:162	ENSG00000148156	Q9Y614	Actin-like protein 7B	gwas
STK35	HGNC:16254	ENSG00000125834	Q8TDR2	Serine/threonine-protein kinase 35	gwas
MAML2	HGNC:16259	ENSG00000184384	Q8IZL2	Mastermind-like protein 2	gwas
PIDD1	HGNC:16491	ENSG00000177595	C0HMD6	PIDD1 alternative open reading frame protein	gwas
CD34	HGNC:1662	ENSG00000174059	P28906	Hematopoietic progenitor cell antigen CD34	gwas
MRPS31	HGNC:16632	ENSG00000102738	Q92665	Small ribosomal subunit protein mS31	gwas
RAB3GAP1	HGNC:17063	ENSG00000115839	Q15042	Rab3 GTPase-activating protein catalytic subunit	gwas
DAB2IP	HGNC:17294	ENSG00000136848	Q5VWQ8	Disabled homolog 2-interacting protein	clinvar
TP53INP1	HGNC:18022	ENSG00000164938	Q96A56	Tumor protein p53-inducible nuclear protein 1	gwas
CAMTA2	HGNC:18807	ENSG00000108509	O94983	Calmodulin-binding transcription activator 2	gwas
CHRNE	HGNC:1966	ENSG00000108556	Q04844	Acetylcholine receptor subunit epsilon	gwas
SLC25A22	HGNC:19954	ENSG00000177542	Q9H936	Mitochondrial glutamate carrier 1	gwas
TIPE3	HGNC:20620	ENSG00000183578	Q5GJ75	Tumor necrosis factor alpha-induced protein 8-like protein 3	gwas
EPS8L2	HGNC:21296	ENSG00000177106	Q9H6S3	Epidermal growth factor receptor kinase substrate 8-like protein 2	gwas
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	gwas
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	gwas
COL5A2	HGNC:2210	ENSG00000204262	P05997	Collagen alpha-2(V) chain	clinvar
COL6A1	HGNC:2211	ENSG00000142156	P12109	Collagen alpha-1(VI) chain	gwas
NANOS1	HGNC:23044	ENSG00000188613	Q8WY41	Nanos homolog 1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
ZNF469	Zinc finger protein 469	May be involved in transcriptional regulation.
ALDH3A1	Aldehyde dehydrogenase, dimeric NADP-preferring	ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde.
DOCK9	Dedicator of cytokinesis protein 9	Guanine nucleotide-exchange factor (GEF) that activates CDC42 by exchanging bound GDP for free GTP.
RORA	Nuclear receptor ROR-alpha	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RPLP2	Large ribosomal subunit protein P2	Plays an important role in the elongation step of protein synthesis.
BHLHE40	Class E basic helix-loop-helix protein 40	Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes.
RXRA	Retinoic acid receptor RXR-alpha	Receptor for retinoic acid that acts as a transcription factor.
SGCA	Alpha-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SLC25A15	Mitochondrial ornithine transporter 1	Mitochondrial ornithine-citrulline antiporter.
TALDO1	Transaldolase	Catalyzes the rate-limiting step of the non-oxidative phase in the pentose phosphate pathway.
TFAP2B	Transcription factor AP-2-beta	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
THRB	Thyroid hormone receptor beta	Nuclear hormone receptor that can act as a repressor or activator of transcription.
TRA	M1-specific T cell receptor alpha chain	The alpha chain of TRAV2701J4201C01/TRBV1901J2S701C02 alpha-beta T cell receptor (TR) clonotype that is specific for HLA-A*02:01-restricted M/matrix protein 1 immunodominant epitope GILGFVFTL of influenza A virus (IAV).
TRB	M1-specific T cell receptor beta chain	The beta chain of TRAV2701J4201C01/TRBV1901J2S701C02 alpha-beta T cell receptor (TR) clonotype that is specific for HLA-A*02:01-restricted M/matrix protein 1 immunodominant epitope GILGFVFTL of influenza A virus (IAV).
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
WBP4	WW domain-binding protein 4	Involved in pre-mRNA splicing as a component of the spliceosome.
WNT1	Proto-oncogene Wnt-1	Ligand for members of the frizzled family of seven transmembrane receptors.
ZFP3	Zinc finger protein 3 homolog	May be involved in transcriptional regulation.
DOP1B	Protein DOP1B	May play a role in regulating membrane trafficking of cargo proteins.
BANP	Protein BANP	Controls V(D)J recombination during T-cell development by repressing T-cell receptor (TCR) beta enhancer function.
C8G	Complement component C8 gamma chain	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.
FBXW5	F-box/WD repeat-containing protein 5	Substrate recognition component of both SCF (SKP1-CUL1-F-box protein) and DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes.
UBXN4	UBX domain-containing protein 4	Involved in endoplasmic reticulum-associated protein degradation (ERAD).
COL5A3	Collagen alpha-3(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
SKAP1	Src kinase-associated phosphoprotein 1	Positively regulates T-cell receptor signaling by enhancing the MAP kinase pathway.
CCNE2	G1/S-specific cyclin-E2	Essential for the control of the cell cycle at the late G1 and early S phase.
MAML2	Mastermind-like protein 2	Acts as a transcriptional coactivator for NOTCH proteins.
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.
RAB3GAP1	Rab3 GTPase-activating protein catalytic subunit	Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
DAB2IP	Disabled homolog 2-interacting protein	Functions as a scaffold protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.
TP53INP1	Tumor protein p53-inducible nuclear protein 1	Antiproliferative and proapoptotic protein involved in cell stress response which acts as a dual regulator of transcription and autophagy.
CAMTA2	Calmodulin-binding transcription activator 2	Transcription activator.
CHRNE	Acetylcholine receptor subunit epsilon	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
SLC25A22	Mitochondrial glutamate carrier 1	Mitochondrial glutamate/H(+) symporter.
TIPE3	Tumor necrosis factor alpha-induced protein 8-like protein 3	Acts as a lipid transfer protein.
EPS8L2	Epidermal growth factor receptor kinase substrate 8-like protein 2	Stimulates guanine exchange activity of SOS1.
COL12A1	Collagen alpha-1(XII) chain	Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.
COL4A1	Collagen alpha-1(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.
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
COL5A2	Collagen alpha-2(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
COL6A1	Collagen alpha-1(VI) chain	Collagen VI acts as a cell-binding protein.
NANOS1	Nanos homolog 1	May act as a translational repressor which regulates translation of specific mRNAs by forming a complex with PUM2 that associates with the 3’-UTR of mRNA targets.
NANOGP8	Homeobox protein NANOGP8	May act as a transcription regulator.
CEND1	Cell cycle exit and neuronal differentiation protein 1	Involved in neuronal differentiation.
CSNK1E	Casein kinase I isoform epsilon	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.
RNF167	E3 ubiquitin-protein ligase RNF167	E3 ubiquitin-protein ligase that acts as a regulator of the TORC1 signaling pathway.
FNDC3B	Fibronectin type III domain-containing protein 3B	May be a positive regulator of adipogenesis.
UCMA	Unique cartilage matrix-associated protein	May be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilage-bone interface.
AAGAB	Alpha- and gamma-adaptin-binding protein p34	May be involved in endocytic recycling of growth factor receptors such as EGFR.

Protein-family classification

Druggable: 13 · Difficult: 14 · Unknown: 48 · Druggable fraction: 0.17

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	3	15.4×	0.009
Antibody/Immunoglobulin	5	1.9×	0.343
Other/Unknown	48	1.1×	0.343
Scaffold/PPI	6	1.4×	0.599
Transporter	1	1.0×	0.975
Transcription factor	8	0.9×	0.975
Kinase	2	0.7×	0.975
Protease	1	0.5×	0.985
Enzyme (other)	1	0.2×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
ZNF469	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF469
ALDH3A1	Enzyme (other)	yes	1.2.1.5	Aldehyde_DH_NAD(P), Aldehyde_DH_dom, Ald_DH_CS_CYS
DOCK9	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, ARM-type_fold
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RPLP2	Other/Unknown	no		Ribosomal_P1/P2, P1/P2_N_sf, Ribosomal_P2_euk
BHLHE40	Transcription factor	no		Orange_dom, bHLH_dom, HLH_DNA-bd_sf
RXRA	Nuclear receptor	yes		Retinoid-X_rcpt/HNF4, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
SGCA	Other/Unknown	no		Cadg, Sarcoglycan_alpha/epsilon, Cadherin-like_sf
SLC25A15	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, Mitochondrial_Carrier
SPAG7	Other/Unknown	no		R3H_dom, SPAG7, R3H_sperm-antigen
TALDO1	Other/Unknown	no		TAL/FSA, Transaldolase_1, Aldolase_TIM
TFAP2B	Transcription factor	no		TF_AP2, TF_AP2_beta, TF_AP2_C
THRB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
TRA	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
TRB	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig_sub, Ig-like_dom
TSC1	Other/Unknown	no		Hamartin
WBP4	Transcription factor	no		Matrin/U1-C_Znf_C2H2, WW_dom, Matrin/U1-like-C_Znf_C2H2
WNT1	Other/Unknown	no		Wnt, Wnt1, Wnt_CS
ZFP3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZnF_C2H2-type_TF
DOP1B	Other/Unknown	no		DOP1_N, DOP1, DOP1_C
BANP	Other/Unknown	no		BEN_domain, BANP
C8G	Other/Unknown	no		Lipocln_cytosolic_FA-bd_dom, A1-microglobln, Calycin
FBXW5	Scaffold/PPI	no		WD40_rpt, F-box_dom, WD40/YVTN_repeat-like_dom_sf
MRPS14	Other/Unknown	no		Ribosomal_uS14
UBXN4	Other/Unknown	no		UBX_dom, Ubiquitin-like_domsf, Thioredoxin-like_sf
COL5A3	Other/Unknown	no		Fib_collagen_C, Collagen, ConA-like_dom_sf
VANGL1	Other/Unknown	no		VANGL
SKAP1	Scaffold/PPI	no		SH3_domain, PH_domain, PH-like_dom_sf
CCNE2	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
ACTL7B	Other/Unknown	no		Actin, ATPase_NBD
STK35	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MAML2	Other/Unknown	no		Mastermind-like_N, MAML1-3, MAML_N_sf
PIDD1	Protease	yes		Death_dom, ZU5_dom, Leu-rich_rpt
CD34	Other/Unknown	no		CD34, CD34/Podocalyxin
MRPS31	Other/Unknown	no		MRP-S31
RAB3GAP1	Other/Unknown	no		Rab3GAP1_conserved, Rab3GAP1_C, Rab3GAP1
DAB2IP	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom
TP53INP1	Other/Unknown	no		TP53INP
CAMTA2	Antibody/Immunoglobulin	yes		IPT_dom, CG-1_dom, Ig-like_fold
CHRNE	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
SLC25A22	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
TIPE3	Other/Unknown	no		TNFAIP8-like, TNFAIP8_sf
EPS8L2	Scaffold/PPI	no		SH3_domain, PTB/PI_dom, PH-like_dom_sf
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL5A2	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL6A1	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
NANOS1	Transcription factor	no		Nanos/Xcar2, Znf_nanos-typ, Nanos_sf

Expression context

Cohort genes with no expression data: 2.

62 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)	73
unknown	2

Top tissues across cohort

Tissue	Cohort genes
oocyte	8
apex of heart	7
secondary oocyte	7
left testis	6
right hemisphere of cerebellum	6
cartilage tissue	5
calcaneal tendon	5
tendon of biceps brachii	5
sperm	5
right uterine tube	5
male germ line stem cell (sensu Vertebrata) in testis	5
skin of hip	4
stromal cell of endometrium	4
tibia	4
lower esophagus mucosa	4
primordial germ cell in gonad	4
granulocyte	4
sural nerve	4
cerebellar hemisphere	4
periodontal ligament	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
ZNF469	211	broad	yes	tibia, upper arm skin, cartilage tissue
ALDH3A1	204	broad	marker	nasal cavity epithelium, trachea, lower esophagus mucosa
DOCK9	293	ubiquitous	marker	calcaneal tendon, right lung, corpus callosum
RORA	284	ubiquitous	marker	upper leg skin, lateral nuclear group of thalamus, skin of hip
RPLP2	295	ubiquitous	marker	nipple, primordial germ cell in gonad, skin of hip
BHLHE40	302	ubiquitous	marker	saphenous vein, vena cava, lower esophagus mucosa
RXRA	294	ubiquitous	marker	skin of hip, gingival epithelium, pancreatic ductal cell
SGCA	190	broad	marker	hindlimb stylopod muscle, gastrocnemius, apex of heart
SLC25A15	198	ubiquitous	marker	liver, right lobe of liver, duodenum
SPAG7	295	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius
TALDO1	294	ubiquitous	marker	trabecular bone tissue, blood, gingival epithelium
TFAP2B	128	broad	marker	corpus epididymis, cauda epididymis, oocyte
THRB	267	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, tibia
TRA
TRB
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
WBP4	293	ubiquitous	marker	oocyte, secondary oocyte, amniotic fluid
WNT1	73	tissue_specific	yes	granulocyte, nucleus accumbens, superior frontal gyrus
ZFP3	221	ubiquitous	yes	cardiac muscle of right atrium, epithelial cell of pancreas, left ventricle myocardium
DOP1B	224	ubiquitous	marker	cortical plate, ganglionic eminence, rectum
BANP	277	ubiquitous	marker	oocyte, secondary oocyte, blood
C8G	164	tissue_specific	marker	right lobe of liver, liver, primordial germ cell in gonad
FBXW5	220	ubiquitous	marker	right testis, left testis, apex of heart
MRPS14	287	ubiquitous	marker	tendon of biceps brachii, endothelial cell, oocyte
UBXN4	303	ubiquitous	marker	sperm, pylorus, cardia of stomach
COL5A3	240	broad	marker	sural nerve, apex of heart, endocervix
VANGL1	234	ubiquitous	marker	bronchial epithelial cell, corpus epididymis, caput epididymis
SKAP1	189	broad	marker	granulocyte, right lobe of liver, right uterine tube
CCNE2	233	ubiquitous	marker	endometrium epithelium, corpus callosum, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 35.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC1	5,445
COL1A1	5,341
CD34	4,928
ALDH3A1	3,940
RPLP2	3,763
TALDO1	3,738
MRPS14	3,690
RXRA	3,421
COL6A1	3,049
COL4A1	2,909

Intra-cohort edges

A	B	Sources
BANP	FNDC3B	string_interaction
BANP	ZNF469	string_interaction
BHLHE40	CSNK1E	string_interaction
CD34	SPAG7	string_interaction
COL12A1	COL1A1	string_interaction
COL12A1	COL5A2	string_interaction
COL12A1	COL5A3	string_interaction
COL12A1	COL6A1	string_interaction
COL1A1	COL5A1	intact, string_interaction
COL1A1	COL5A2	string_interaction
COL1A1	COL6A1	string_interaction
COL4A1	COL5A1	string_interaction
COL4A1	COL5A2	string_interaction
COL4A1	COL5A3	string_interaction
COL4A1	COL6A1	string_interaction
COL5A1	COL5A2	string_interaction
COL5A1	COL5A3	string_interaction
COL5A1	COL6A1	intact
COL5A1	ZNF469	string_interaction
COL5A2	COL5A3	string_interaction
COL5A2	COL6A1	string_interaction
COL5A3	COL6A1	string_interaction
COL5A3	TSC1	string_interaction
CSNK1E	RORA	biogrid_interaction
DOCK9	RAB3GAP1	string_interaction
DOCK9	ZNF469	string_interaction
FBXW5	SRFBP1	biogrid_interaction, intact
FBXW5	TIPE3	string_interaction
FBXW5	TSC1	string_interaction
FNDC3B	LCN12	string_interaction
FNDC3B	ZNF469	string_interaction
LCN12	ZNF469	string_interaction
MRPS31	WBP4	string_interaction
RAB3GAP1	ZNF469	string_interaction
RXRA	THRB	biogrid_interaction, intact

Structural data

PDB: 37 · AlphaFold-only: 38 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RXRA	P19793	110
MRPS14	O60783	77
MRPS31	Q92665	76
THRB	P10828	34
TRB	P0DSE2	23
C8G	P07360	15
COL1A1	P02452	14
TRA	P0DSE1	13
CHRNE	Q04844	13
WBP4	O75554	11
INTS8	Q75QN2	10
RPLP2	P05387	8
ALDH3A1	P30838	7
AIFM3	Q96NN9	7
TSC1	Q92574	5
DOCK9	Q9BZ29	4
BANP	Q8N9N5	4
VANGL1	Q8TAA9	4
COL4A1	P02462	4
RORA	P35398	3
AAGAB	Q6PD74	3
EPS8L2	Q9H6S3	2
CSNK1E	P49674	2
GATD1	Q8NB37	2
SPAG7	O75391	1
TALDO1	P37837	1
TFAP2B	Q92481	1
UBXN4	Q92575	1
SKAP1	Q86WV1	1
CCNE2	O96020	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DENND10P1	Q6NSW5	90.55
NAA16	Q6N069	89.49
ACTL7B	Q9Y614	88.35
NDUFAF6	Q330K2	87.70
SLC25A15	Q9Y619	87.43
LCN12	Q6JVE5	86.62
WNT1	P04628	86.53
FBXW5	Q969U6	84.64
SLC52A1	Q9NWF4	84.13
UCMA	Q8WVF2	82.20
SLC47A2	Q86VL8	82.05
SPATA17	Q96L03	81.98
SGCA	Q16586	80.15
RNF167	Q9H6Y7	79.08
SLC25A22	Q9H936	78.48
FAM76B	Q5HYJ3	76.41
FNDC3B	Q53EP0	75.78
ZFP3	Q96NJ6	75.03
PNPLA2	Q96AD5	72.56
DOP1B	Q9Y3R5	72.36
RAB11FIP4	Q86YS3	72.35
STK35	Q8TDR2	67.52
DAB2IP	Q5VWQ8	65.74
SRFBP1	Q8NEF9	62.20
CD34	P28906	60.99
CEND1	Q8N111	60.87
CAMTA2	O94983	60.82
INCA1	Q0VD86	60.75
BHLHE40	O14503	60.60
TP53INP1	Q96A56	58.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 450. Enrichment computed across 118 evidence-associated genes (82 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 82 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Assembly of collagen fibrils and other multimeric structures	8	19.6×	3e-06	COL1A1, COL5A3, COL12A1, COL4A1, COL5A1, COL5A2, COL6A1, LOX
Collagen chain trimerization	7	22.2×	4e-06	COL1A1, COL5A3, COL12A1, COL4A1, COL5A1, COL5A2, COL6A1
Collagen biosynthesis and modifying enzymes	8	16.6×	4e-06	COL1A1, COL5A3, COL12A1, COL4A1, COL5A1, COL5A2, COL6A1, PLOD1
Fibronectin matrix formation	5	34.8×	3e-05	COL1A1, COL5A3, COL4A1, COL5A1, COL5A2
Collagen degradation	7	15.0×	3e-05	COL1A1, COL5A3, COL12A1, COL4A1, COL5A1, COL5A2, COL6A1
Syndecan interactions	5	25.8×	7e-05	COL1A1, COL5A3, COL5A1, COL5A2, ITGA2
Non-integrin membrane-ECM interactions	7	13.2×	7e-05	COL1A1, SGCA, COL5A3, COL4A1, COL5A1, COL5A2, ITGA2
ECM proteoglycans	7	12.8×	7e-05	COL1A1, COL5A3, COL4A1, COL5A1, COL5A2, COL6A1, ITGA2
MET activates PTK2 signaling	5	23.2×	1e-04	COL1A1, COL5A3, COL5A1, COL5A2, ITGA2
Integrin cell surface interactions	7	11.5×	1e-04	COL1A1, COL5A3, COL4A1, COL5A1, COL5A2, COL6A1, ITGA2
Signaling by PDGF	5	15.5×	7e-04	COL5A3, COL4A1, COL5A1, COL5A2, COL6A1
Attachment of bacteria to epithelial cells	4	24.2×	7e-04	COL5A3, COL4A1, COL5A1, COL5A2
NCAM1 interactions	5	15.1×	7e-04	COL5A3, COL4A1, COL5A1, COL5A2, COL6A1
R-HSA-400253	4	16.9×	0.003	RORA, BHLHE40, RXRA, CSNK1E
Platelet Adhesion to exposed collagen	3	24.6×	0.007	COL1A1, GP1BA, ITGA2
Crosslinking of collagen fibrils	3	20.9×	0.010	COL1A1, COL4A1, LOX
Developmental Lineage of Pancreatic Ductal Cells	4	11.1×	0.012	COL1A1, COL5A3, COL5A1, COL5A2
Enhanced binding of GP1BA variant to VWF multimer:collagen	2	39.8×	0.025	COL1A1, GP1BA
Defective binding of VWF variant to GPIb:IX:V	2	39.8×	0.025	COL1A1, GP1BA
SUMO E3 ligases SUMOylate target proteins	4	8.7×	0.025	RORA, RXRA, TFAP2B, THRB
Disassembly of the destruction complex and recruitment of AXIN to the membrane	3	13.1×	0.032	WNT1, FZD2, LRP6
SUMOylation	4	8.0×	0.032	RORA, RXRA, TFAP2B, THRB
Calcineurin activates NFAT	2	30.9×	0.034	NFATC3, PPP3CA
SUMOylation of intracellular receptors	3	12.3×	0.034	RORA, RXRA, THRB
CLEC7A (Dectin-1) induces NFAT activation	2	25.3×	0.048	NFATC3, PPP3CA
GP1b-IX-V activation signalling	2	23.2×	0.055	COL1A1, GP1BA
RNA Polymerase II Transcription	10	2.8×	0.055	RORA, RXRA, TFAP2B, THRB, BANP, CCNE2, MAML2, TP53INP1 (+2 more)
Gastrulation	3	9.5×	0.061	TFAP2B, MAML2, SMAD3
Anchoring fibril formation	2	18.6×	0.077	COL1A1, COL4A1
TCF dependent signaling in response to WNT	4	5.7×	0.077	WNT1, CSNK1E, FZD2, LRP6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 108 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen fibril organization	10	20.8×	4e-08	COL1A1, COL5A3, COL12A1, COL4A1, COL5A1, COL5A2, COL6A1, LOX (+2 more)
rhombomere 4 development	2	156.0×	0.011	HOXB1, HOXB2
negative regulation of endodermal cell differentiation	2	156.0×	0.011	COL5A1, COL5A2
detection of tumor cell	2	104.0×	0.011	TRA, TRB
T cell mediated cytotoxicity directed against tumor cell target	2	104.0×	0.011	TRA, TRB
regulation of cell-matrix adhesion	3	36.0×	0.011	TSC1, NF1, PKHD1
collagen biosynthetic process	3	29.3×	0.011	COL1A1, COL5A1, PLOD1
negative regulation of fibroblast proliferation	4	18.4×	0.011	DAB2IP, TP53INP1, INCA1, NF1
skin development	4	16.4×	0.011	TFAP2B, COL5A3, COL5A1, COL5A2
canonical Wnt signaling pathway	6	8.5×	0.011	WNT1, COL6A1, CSNK1E, FOXO1, FZD2, LRP6
positive regulation of DNA-templated transcription	13	3.4×	0.011	COL1A1, RORA, RXRA, TFAP2B, WNT1, SKAP1, TP53INP1, NAA16 (+5 more)
positive regulation of transcription by RNA polymerase II	19	2.6×	0.011	RORA, RXRA, TFAP2B, THRB, WNT1, SKAP1, MAML2, DAB2IP (+11 more)
positive regulation of thyroid hormone receptor signaling pathway	2	78.0×	0.017	RXRA, THRB
eye morphogenesis	2	78.0×	0.017	COL5A1, COL5A2
calcineurin-NFAT signaling cascade	3	23.4×	0.017	NFATC3, PPP3CA, PPP3CC
negative regulation of calcium ion import across plasma membrane	2	62.4×	0.023	PPP3CA, PPP3CC
negative regulation of fat cell differentiation	4	11.6×	0.023	RORA, WNT1, FOXO1, SMAD3
cellular response to amino acid stimulus	4	11.3×	0.023	COL1A1, COL4A1, COL5A2, COL6A1
regulation of striated muscle tissue development	2	52.0×	0.031	LOX, SMAD3
transdifferentiation	2	39.0×	0.051	CD34, SMAD3
regulation of calcium ion transmembrane transport	2	39.0×	0.051	ATP1B1, PIK3CG
facial nerve structural organization	2	34.7×	0.058	HOXB1, HOXB2
regulation of megakaryocyte differentiation	2	34.7×	0.058	EIF6, LOX
negative regulation of cardiac muscle hypertrophy in response to stress	2	34.7×	0.058	FOXO1, SMAD3
positive regulation of calcium ion import across plasma membrane	2	31.2×	0.064	PPP3CA, PPP3CC
excitatory postsynaptic potential	3	12.3×	0.064	RAB3GAP1, GRIN2B, PPP3CA
phosphatidylinositol 3-kinase/protein kinase B signal transduction	4	7.8×	0.064	COL6A1, IGF1R, NF1, PIK3CG
adaptive immune response	6	4.7×	0.064	TRA, TRB, TSC1, SKAP1, CD46, PIK3CG
osteoblast differentiation	5	5.6×	0.067	COL1A1, COL6A1, UCMA, LOX, NF1
calcineurin-mediated signaling	2	28.4×	0.070	PPP3CA, PPP3CC

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Riboflavin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Hydroxocobalamin, Mitomycin.

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 8 · Phased (≥1): 9 · Undrugged: 66

Druggability breadth: 47 of 118 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
RORA	TRETINOIN
RXRA	BEXAROTENE
THRB	AMINOCAPROIC ACID
CCNE2	PALBOCICLIB
STK35	NERATINIB
CHRNE	MECAMYLAMINE
CSNK1E	AFATINIB
SLC47A2	EPINASTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THRB	117	4
CSNK1E	37	4
SLC47A2	28	4
RXRA	23	4
STK35	18	4
CCNE2	12	4
CHRNE	4	4
RORA	2	4
WNT1	1	1
COL1A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORA, RXRA
BEXAROTENE	4	RXRA
OXAPROZIN	4	RXRA
PITAVASTATIN CALCIUM	4	RXRA
SULINDAC	4	RXRA
LEVOTHYROXINE	4	RXRA, THRB
DOMPERIDONE	4	RXRA, SLC47A2
FLUVASTATIN	4	RXRA
ALITRETINOIN	4	RXRA
ROSIGLITAZONE MALEATE	4	RXRA
PIOGLITAZONE HYDROCHLORIDE	4	RXRA
MECLOFENAMIC ACID	4	RXRA
CALCITRIOL	4	RXRA
AMINOCAPROIC ACID	4	THRB
INDIGOTINDISULFONATE	4	THRB
CHLORMADINONE ACETATE	4	THRB
AMOXAPINE	4	THRB
IDARUBICIN	4	THRB
DYCLONINE HYDROCHLORIDE	4	THRB
ISOSORBIDE	4	THRB
CLOMIPRAMINE HYDROCHLORIDE	4	THRB
CHLORMEZANONE	4	THRB
PHENOXYBENZAMINE HYDROCHLORIDE	4	THRB
METHYSERGIDE MALEATE	4	THRB
LIOTHYRONINE SODIUM	4	THRB
DYCLONINE	4	THRB
ROSE BENGAL FREE ACID	4	THRB
INAMRINONE	4	THRB
MOLSIDOMINE	4	THRB
METRONIDAZOLE	4	THRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
RXRA	846	Binding:703, Functional:138, ADMET:5
CSNK1E	420	Binding:416, ADMET:2, Functional:2
THRB	169	Binding:129, Functional:40
CCNE2	159	Binding:159
RORA	115	Binding:111, Functional:3, Unclassified:1
STK35	94	Binding:94
ALDH3A1	42	Binding:38, ADMET:4
CHRNE	28	Binding:26, Functional:2
SLC47A2	17	Binding:14, ADMET:3
WNT1	10	Binding:10
COL1A1	8	Binding:8
DAB2IP	8	Binding:8
INTS8	6	Binding:6
PNPLA2	5	Binding:5
RPLP2	2	Binding:2
TALDO1	1	Binding:1
ZFP3	1	Binding:1
UBXN4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH3A1	1.2.1.5	aldehyde dehydrogenase [NAD(P)+]
CSNK1E	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RORA	115
RXRA	846
THRB	169
CCNE2	159
CSNK1E	420

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; 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	RORA, RXRA
BEXAROTENE	4	RXRA
OXAPROZIN	4	RXRA
PITAVASTATIN CALCIUM	4	RXRA
SULINDAC	4	RXRA
LEVOTHYROXINE	4	RXRA, THRB
DOMPERIDONE	4	RXRA, SLC47A2
FLUVASTATIN	4	RXRA
ALITRETINOIN	4	RXRA
ROSIGLITAZONE MALEATE	4	RXRA
PIOGLITAZONE HYDROCHLORIDE	4	RXRA
MECLOFENAMIC ACID	4	RXRA
CALCITRIOL	4	RXRA
AMINOCAPROIC ACID	4	THRB
INDIGOTINDISULFONATE	4	THRB
CHLORMADINONE ACETATE	4	THRB
AMOXAPINE	4	THRB
IDARUBICIN	4	THRB
DYCLONINE HYDROCHLORIDE	4	THRB
ISOSORBIDE	4	THRB
CLOMIPRAMINE HYDROCHLORIDE	4	THRB
CHLORMEZANONE	4	THRB
PHENOXYBENZAMINE HYDROCHLORIDE	4	THRB
METHYSERGIDE MALEATE	4	THRB
LIOTHYRONINE SODIUM	4	THRB
DYCLONINE	4	THRB
ROSE BENGAL FREE ACID	4	THRB
INAMRINONE	4	THRB
MOLSIDOMINE	4	THRB
METRONIDAZOLE	4	THRB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	RORA, RXRA, THRB, CCNE2, STK35, CHRNE, CSNK1E, SLC47A2
B	Phased (≥1) drug, not yet approved	1	WNT1
C	Druggable family + PDB, no drug	5	ALDH3A1, TRA, TRB, PIDD1, COL12A1
D	Druggable family + AlphaFold only, no drug	3	CAMTA2, SLC25A22, FNDC3B
E	Difficult family or no structure, no drug	58	COL1A1, ZNF469, DOCK9, RPLP2, BHLHE40, SGCA, SLC25A15, SPAG7, TALDO1, TFAP2B (+48 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL1A1	8	—
ZNF469	0	—
ALDH3A1	42	—
DOCK9	0	—
RPLP2	2	—
BHLHE40	0	—
SGCA	0	—
SLC25A15	0	—
SPAG7	0	—
TALDO1	1	—
TFAP2B	0	—
TRA	0	—
TRB	0	—
TSC1	0	—
WBP4	0	—
ZFP3	1	—
DOP1B	0	—
BANP	0	—
C8G	0	—
FBXW5	0	—
MRPS14	0	—
UBXN4	1	—
COL5A3	0	—
VANGL1	0	—
SKAP1	0	—
ACTL7B	0	—
MAML2	0	—
PIDD1	0	—
CD34	0	—
MRPS31	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 279.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	197
PHASE3	30
PHASE2	20
PHASE2/PHASE3	11
PHASE1/PHASE2	8
PHASE4	6
PHASE1	5
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT01604135	PHASE3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT03922542	PHASE2/PHASE3	RECRUITING	Comparison of Standard vs. Accelerated Corneal Crosslinking
NCT06100939	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06100952	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age with Keratoconus
NCT06450470	PHASE3	RECRUITING	Use of a Freeze-dried Amniotic Membrane Post Crosslinking in Subjects With Progressive Keratoconus
NCT06601101	PHASE3	RECRUITING	Effects of Topical Insulin on Corneal Epithelium Healing After Corneal Crosslinking in Patients With Keratoconus
NCT07124910	PHASE3	RECRUITING	Comparison of Epi-ON Corneal Collagen Crosslinking Performed Using an 18-Minute UVA Exposure vs. a 24-Minute UVA Exposure on Eyes With Ectatic Corneal Diseases
NCT07135167	PHASE3	RECRUITING	Compassionate Use Study of Epi-ON Corneal Collagen Crosslinking Performed Using UVA Exposure on Eyes With Ectatic Corneal Diseases for Subjects With Down Syndrome
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00435799	PHASE2/PHASE3	UNKNOWN	Evaluating Collagen Cross-Linking (CCL) Treatment in Norway
NCT00567671	PHASE2/PHASE3	COMPLETED	Corneal Collagen Cross-Linking for the Treatment of Progressive Keratoconus and Corneal Ectasia
NCT00626717	PHASE2/PHASE3	COMPLETED	Riboflavin Mediated Corneal Crosslinking for Stabilizing Progression of Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00679666	PHASE2/PHASE3	WITHDRAWN	Corneal Crosslinking in Keratoconus and Corneal Ectasia
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00841386	PHASE2/PHASE3	UNKNOWN	Treatment of Keratoconus Using Collagen Cross-Linking
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01081561	PHASE2/PHASE3	UNKNOWN	Collagen Cross-Linking for Keratoconus/Ectasia With and Without Intacs
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	PHASE3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	PHASE3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	PHASE3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01643226	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	PHASE3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	PHASE3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01743443	PHASE2/PHASE3	COMPLETED	Corneal Sensitivity Cross-linking Keratoconus
NCT01972854	PHASE3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	PHASE3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	PHASE3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	PHASE3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	PHASE3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RIBOFLAVIN	4	33
FLUOROMETHOLONE ACETATE	4	2
PREDNISOLONE ACETATE	4	2
DEXAMETHASONE SODIUM PHOSPHATE	4	1
HEXACHLOROPHENE	4	1
INSULIN HUMAN	4	1
LOTEPREDNOL ETABONATE	4	1
RIBOFLAVIN 5’-PHOSPHATE	4	1
DEXTRAN	3	1
DEXTRAN 1	2	1
CHEMBL511565	0	33
CHEMBL5267279	0	33
CHEMBL1200637	0	1
CHEMBL4743806	0	1