Cataract

Summary

Cataract (MONDO:0005129) is a disease (an umbrella term covering 29 Mondo subtypes) caused by variants in CYP51A1, FOXE3, VIM, and 1 other genes, with 75 cohort genes (296 GWAS associations across 108 studies) and 1,206 clinical trials. Top therapeutic interventions include bromfenac, ketorolac, and moxifloxacin.

At a glance

• Causal genes: CYP51A1 (GenCC Definitive), FOXE3 (GenCC Definitive), VIM (GenCC Definitive), RRAGA (GenCC Strong)
• Umbrella term: 29 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 296
• ClinVar variants: 87
• Clinical trials: 1,206

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cataract
Mondo ID	MONDO:0005129
MeSH	D002386
OMIM	116200
DOID	DOID:83
ICD-11	109841337
NCIT	C26713
SNOMED CT	193570009
UMLS	C0086543
MedGen	39462
Is cancer (heuristic)	no

Also known as: cataract · cataract (disease) · opacity of the lens

Data availability: 87 ClinVar variants · 296 GWAS associations (108 studies) · 13 GenCC gene-disease records · 1 HPO phenotype · 1 cell line.

Disease family

An umbrella term covering 29 Mondo subtypes.

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

Related subtypes (9): lens subluxation, posterior dislocation of lens, blepharoptosis-myopia-ectopia lentis syndrome, classic homocystinuria, facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome, congenital primary aphakia, ectopia lentis-chorioretinal dystrophy-myopia syndrome, isolated ectopia lentis, encephalopathy due to sulfite oxidase deficiency

Subtypes (29): immature cataract, diabetic cataract, mature cataract, tetanic cataract, myotonic cataract, senile cataract, diabetes mellitus type 2 associated cataract, cataract 4 multiple types, cataract 29, cataract 1 multiple types, early-onset non-syndromic cataract, cataract 3 multiple types, cataract 9 multiple types, cataract 28, cataract 18, cataract 12 multiple types, cataract 34 multiple types, cataract 36, bhaskar jagannathan syndrome, autosomal dominant cataract, craniostenosis cataract, Kozlowski Rafinski Klicharska syndrome, cataract 49, cataract 48, hypermature cataract, nuclear cataract, cortical cataract, cataract 2, multiple types, cataract 50 with or without glaucoma

Genetics & variants

GWAS landscape

296 GWAS associations across 108 studies. Top hits map to 24 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs17172647	5e-76	ZNF619P1 - HMGN1P19	G	1.07
rs4814857	2e-70	SLC24A3	G	1.09
rs150648223	7e-60	SMIM38 - MYEOV	ATTT	1.1
chr4:173984049	2e-45		T	1.16
rs9895741	1e-42	NPLOC4	G	0.95
chr20:19476624	6e-34		G	0.11
rs12593	2e-33	COQ8A	T	1.04
rs9842371	3e-33	SOX2-OT	T	1.09
rs10663094	2e-32	SOX2-OT	ACT	1.05
rs6046142	4e-30	SLC24A3	G	0.09
rs79721202	5e-28	SMIM38 - MYEOV	?	1.19
rs9038	9e-28	SEPTIN9	C	0.96
rs10500355	6e-26	RBFOX1	A	1.04
rs4451405	6e-25	CDKN2B-AS1	?
rs113439088	5e-24	SOX2-OT	TCTCTC	0.09
rs2274224	6e-24	PLCE1, PLCE1-AS1	C	1.03
chr11:68927358	8e-24		A	0.1
rs73015318	9e-24	QKI	A	1.05
chr11:69179313	7e-23		T	0.11
rs17739338	3e-22	CAPRIN2	T	0.94
rs35198068	4e-22	TCF7L2	T	0.05
rs62621812	5e-22	ZNF800	A	1.12
rs1014607	2e-21	BAMBI - LINC01517	A	0.96
rs6665290	1e-20	CDC42BPA	T	1.05
rs148920596	2e-20	SMIM38 - MYEOV	A	0.1
rs10210444	1e-19	PLB1	A	1.04
rs1679013	2e-19	CDKN2B-AS1	T	1.07
rs112364254	2e-18	NPLOC4	A	1.04
rs140625707	3e-18	DIRC3	C	1.06
chr1:227214745	3e-18		C	0.05

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90018814	Sakaue S	2021	39,519	452,358	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST012013	Choquet H	2021	38,996	283,185	A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects.
GCST90297578	Auwerx C	2024	38,671	279,248	Rare copy-number variants as modulators of common disease susceptibility.
GCST90297632	Auwerx C	2024	38,671	279,248	Rare copy-number variants as modulators of common disease susceptibility.
GCST90297685	Auwerx C	2024	38,671	279,248	Rare copy-number variants as modulators of common disease susceptibility.
GCST90297729	Auwerx C	2024	38,671	279,248	Rare copy-number variants as modulators of common disease susceptibility.
GCST90018594	Sakaue S	2021	38,194	140,532	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST012012	Choquet H	2021	28,092	50,487	A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects.
GCST90014268	Choquet H	2021	28,092	50,487	A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects.
GCST90013708	Ishigaki K	2020	24,622	187,831	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	2
Tier 3: regulatory	2
Tier 4: intronic/intergenic	43

MAF distribution

Bucket	Variants
common (>=0.05)	41
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	8

Functional consequences

Consequence	Count
intron_variant	31
unknown	9
missense_variant	3
regulatory_region_variant	2
intergenic_variant	2
splice_region_variant	1
3_prime_UTR_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs17172647	7	46174655	A>G	0.05	splice_region_variant	ZNF619P1 - HMGN1P19	5e-76	Tier 2: splice/UTR
rs4814857	20	19476624	A>G	0.05	intron_variant	SLC24A3	2e-70	Tier 4: intronic/intergenic
rs150648223	11	69174695	A>ATTT	0.05	intron_variant	SMIM38 - MYEOV	7e-60	Tier 4: intronic/intergenic
chr4:173984049							2e-45	Tier 4: intronic/intergenic
rs9895741	17	81636805	A>C,G	0.05	intron_variant	NPLOC4	1e-42	Tier 4: intronic/intergenic
chr20:19476624							6e-34	Tier 4: intronic/intergenic
rs12593	1	226984589	C>G,T	0.05	missense_variant	COQ8A	2e-33	Tier 1: coding
rs9842371	3	181629149	C>T	0.05	intron_variant	SOX2-OT	3e-33	Tier 4: intronic/intergenic
rs10663094	3	181645677	A>ACT	0.05	intron_variant	SOX2-OT	2e-32	Tier 4: intronic/intergenic
rs6046142	20	19496121	G>A	0.157	intron_variant	SLC24A3	4e-30	Tier 4: intronic/intergenic
rs79721202	11	69173724	T>G	0.094	intron_variant	SMIM38 - MYEOV	5e-28	Tier 4: intronic/intergenic
rs9038	17	77499315	T>C,G	0.05	3_prime_UTR_variant	SEPTIN9	9e-28	Tier 2: splice/UTR
rs10500355	16	7409346	T>A	0.05	intron_variant	RBFOX1	6e-26	Tier 4: intronic/intergenic
rs4451405	9	22071751	C>A,T	0.05	intron_variant	CDKN2B-AS1	6e-25	Tier 4: intronic/intergenic
rs113439088	3	181655855	T>TCTCTTCTCTC		intron_variant	SOX2-OT	5e-24	Tier 4: intronic/intergenic
rs2274224	10	94279840	G>A,C,T	0.05	missense_variant	PLCE1, PLCE1-AS1	6e-24	Tier 1: coding
chr11:68927358				0.106			8e-24	Tier 4: intronic/intergenic
rs73015318	6	163432507	C>A,T	0.05	intron_variant	QKI	9e-24	Tier 4: intronic/intergenic
chr11:69179313							7e-23	Tier 4: intronic/intergenic
rs17739338	12	30731158	C>T	0.05	intron_variant	CAPRIN2	3e-22	Tier 4: intronic/intergenic
rs35198068	10	112995025	T>C	0.296	intron_variant	TCF7L2	4e-22	Tier 4: intronic/intergenic
rs62621812	7	127375029	G>A	0.05	missense_variant	ZNF800	5e-22	Tier 1: coding
rs1014607	10	28735201	G>A	0.05	regulatory_region_variant	BAMBI - LINC01517	2e-21	Tier 3: regulatory
rs6665290	1	227013405	C>G,T	0.05	intron_variant	CDC42BPA	1e-20	Tier 4: intronic/intergenic
rs148920596	11	69176687	A>C,G,T	0.087	intron_variant	SMIM38 - MYEOV	2e-20	Tier 4: intronic/intergenic
rs10210444	2	28637113	G>A	0.05	intron_variant	PLB1	1e-19	Tier 4: intronic/intergenic
rs1679013	9	22206988	C>A,G,T	0.05	intron_variant	CDKN2B-AS1	2e-19	Tier 4: intronic/intergenic
rs112364254	17	81611261	G>A	0.05	intron_variant	NPLOC4	2e-18	Tier 4: intronic/intergenic
rs140625707	2	217665120	CT>C	0.05	intron_variant	DIRC3	3e-18	Tier 4: intronic/intergenic
chr1:227214745				0.389			3e-18	Tier 4: intronic/intergenic

ClinVar germline variants

87 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 19 conflicting classifications of pathogenicity, 11 benign/likely benign, 9 pathogenic, 3 benign, 3 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267868	46;XY;inv(9)(q22.3q34.11)dn		Pathogenic	criteria provided, single submitter
1804039	NM_003571.4(BFSP2):c.449G>A (p.Trp150Ter)	BFSP2	Pathogenic	criteria provided, single submitter
373962	NM_001379500.1(COL18A1):c.929-2A>G	COL18A1	Pathogenic	criteria provided, single submitter
996016	NM_001144061.2(COPB1):c.957+1G>T	COPB1	Pathogenic/Likely pathogenic	no assertion criteria provided
996037	NM_001144061.2(COPB1):c.1651T>G (p.Phe551Val)	COPB1	Pathogenic	criteria provided, single submitter
1704644	NM_004076.5(CRYBB3):c.467G>A (p.Gly156Glu)	CRYBB3	Pathogenic	criteria provided, single submitter
1341682	NM_004431.5(EPHA2):c.41G>A (p.Trp14Ter)	EPHA2	Pathogenic	criteria provided, single submitter
625113	NM_001161748.2(LIM2):c.388C>T (p.Arg130Cys)	LIM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523376	NM_000539.3(RHO):c.891C>G (p.Ser297Arg)	RHO	Pathogenic	criteria provided, multiple submitters, no conflicts
812923	NC_000005.10:g.139189727_139201554del	SIL1	Pathogenic	no assertion criteria provided
373961	NM_001379500.1(COL18A1):c.3448C>T (p.Arg1150Ter)	SLC19A1	Pathogenic	criteria provided, single submitter
523380	NM_000553.6(WRN):c.724+1G>T	WRN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523328	NM_000093.5(COL5A1):c.608G>T (p.Gly203Val)	COL5A1	Likely pathogenic	criteria provided, single submitter
3253728	NM_012244.4(SLC7A8):c.1017-1G>T	SLC7A8	Likely pathogenic	criteria provided, single submitter
167038	NM_005670.4(EPM2A):c.376A>G (p.Ile126Val)	EPM2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
866409	NM_000180.4(GUCY2D):c.2492T>C (p.Leu831Pro)	GUCY2D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156553	NM_018060.4(IARS2):c.2726C>T (p.Pro909Leu)	IARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523564	NM_172250.3(MMAA):c.304G>A (p.Ala102Thr)	MMAA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
582318	NM_017617.5(NOTCH1):c.3334G>A (p.Val1112Ile)	NOTCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283383	NM_000325.6(PITX2):c.639A>T (p.Ser213=)	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347294	NM_000325.6(PITX2):c.*340A>G	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347298	NM_000325.6(PITX2):c.862C>T (p.Leu288=)	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347300	NM_000325.6(PITX2):c.224A>C (p.Gln75Pro)	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
559593	NM_000325.6(PITX2):c.619A>G (p.Met207Val)	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899596	NM_153427.2(PITX2):c.-429C>G	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900591	NM_153427.3(PITX2):c.-79G>A	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900892	NM_153427.2(PITX2):c.-967C>T	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901581	NM_153427.2(PITX2):c.-1385+12T>C	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901637	NM_153427.2(PITX2):c.-1532C>A	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902274	NM_153427.3(PITX2):c.-211G>A	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 36 · Orphanet: 57 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
CYP51A1	Definitive	Autosomal recessive	cataract
FOXE3	Definitive	Autosomal dominant	cataract	14
VIM	Definitive	Autosomal dominant	cataract	4
RRAGA	Strong	Autosomal dominant	cataract
PANK4	Moderate	Autosomal dominant	cataract 49	4
PGRMC1	Moderate	X-linked	cataract	2
AKR1E2	Limited	Autosomal recessive	cataract	2
MFSD6L	Limited	Autosomal recessive	cataract
RNLS	Limited	Autosomal recessive	cataract
TAPT1	Limited	Autosomal recessive	cataract	5
WDR87	Limited	Autosomal recessive	cataract

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VIM	Orphanet:675396	Epithelioid hemangioma
VIM	Orphanet:98984	Pulverulent cataract
PGRMC1	Orphanet:98994	Total early-onset cataract
PANK4	Orphanet:98993	Early-onset posterior polar cataract
CYP51A1	Orphanet:521432	Congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome
TAPT1	Orphanet:457378	Complex lethal osteochondrodysplasia
FOXE3	Orphanet:708	Peters anomaly
FOXE3	Orphanet:83461	Congenital primary aphakia
FOXE3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
RHO	Orphanet:215	Congenital stationary night blindness
RHO	Orphanet:52427	Retinitis punctata albescens
RHO	Orphanet:791	Retinitis pigmentosa
RORA	Orphanet:528084	Non-specific syndromic intellectual disability
BFSP2	Orphanet:441452	Early-onset lamellar cataract
BFSP2	Orphanet:98984	Pulverulent cataract
BFSP2	Orphanet:98985	Early-onset sutural cataract
ATXN7	Orphanet:94147	Spinocerebellar ataxia type 7
BMP4	Orphanet:139471	Microphthalmia with brain and digit anomalies
BMP4	Orphanet:199306	Cleft lip/palate
BMP4	Orphanet:828	Stickler syndrome
BMP4	Orphanet:93100	Renal agenesis, unilateral
SOX2	Orphanet:3157	Septo-optic dysplasia spectrum
SOX2	Orphanet:35612	Nanophthalmos
SOX2	Orphanet:77298	Anophthalmia/microphthalmia-esophageal atresia syndrome
SOX2	Orphanet:98938	Colobomatous microphthalmia
TALDO1	Orphanet:101028	Transaldolase deficiency
WRN	Orphanet:902	Werner syndrome
COQ8A	Orphanet:139485	Autosomal recessive ataxia due to ubiquinone deficiency
PLCE1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
DIRC3	Orphanet:146	Differentiated thyroid carcinoma
DIRC3	Orphanet:422526	Hereditary clear cell renal cell carcinoma
CDKN2B	Orphanet:618	Familial melanoma
CDKN2B	Orphanet:652	Multiple endocrine neoplasia type 1
MMAA	Orphanet:79310	Vitamin B12-responsive methylmalonic acidemia type cblA
UPF3B	Orphanet:776	Lujan-Fryns syndrome
UPF3B	Orphanet:777	X-linked non-syndromic intellectual disability
QKI	Orphanet:251671	Angiocentric glioma
COL18A1	Orphanet:1571	Knobloch syndrome
COL5A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COPB1	Orphanet:633035	Intellectual disability-early-onset cataract-microcephaly syndrome
CPAMD8	Orphanet:519388	Autosomal recessive anterior segment dysgenesis
VPS13C	Orphanet:2828	Young-onset Parkinson disease
CRYBB3	Orphanet:98988	Early-onset anterior polar cataract
CRYBB3	Orphanet:98991	Early-onset nuclear cataract
SIL1	Orphanet:559	Marinesco-Sjögren syndrome
CASZ1	Orphanet:1606	1p36 deletion syndrome
IARS2	Orphanet:436174	Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
IARS2	Orphanet:506	Leigh syndrome
EPHA2	Orphanet:441447	Early-onset posterior subcapsular cataract
EPHA2	Orphanet:98991	Early-onset nuclear cataract

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	46
multi_evidence	29

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VIM	HGNC:12692	ENSG00000026025	P08670	Vimentin	gencc
PGRMC1	HGNC:16090	ENSG00000101856	O00264	Membrane-associated progesterone receptor component 1	gencc
RRAGA	HGNC:16963	ENSG00000155876	Q7L523	Ras-related GTP-binding protein A	gencc
PANK4	HGNC:19366	ENSG00000157881	Q9NVE7	4’-phosphopantetheine phosphatase	gencc
AKR1E2	HGNC:23437	ENSG00000165568	Q96JD6	1,5-anhydro-D-fructose reductase	gencc
RNLS	HGNC:25641	ENSG00000184719	Q5VYX0	Renalase	gencc
CYP51A1	HGNC:2649	ENSG00000001630	Q16850	Lanosterol 14-alpha demethylase	gencc
MFSD6L	HGNC:26656	ENSG00000185156	Q8IWD5	Major facilitator superfamily domain-containing protein 6-like	gencc
TAPT1	HGNC:26887	ENSG00000169762	Q6NXT6	Transmembrane anterior posterior transformation protein 1 homolog	gencc
WDR87	HGNC:29934	ENSG00000171804	Q6ZQQ6	WD repeat-containing protein 87	gencc
FOXE3	HGNC:3808	ENSG00000186790	Q13461	Forkhead box protein E3	gencc
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gwas
BFSP2	HGNC:1041	ENSG00000170819	Q13515	Phakinin	clinvar
BIN3	HGNC:1054	ENSG00000147439	Q9NQY0	Bridging integrator 3	gwas
ATXN7	HGNC:10560	ENSG00000163635	O15265	Ataxin-7	gwas
BMP3	HGNC:1070	ENSG00000152785	P12645	Bone morphogenetic protein 3	gwas
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	gwas
SLC19A1	HGNC:10937	ENSG00000173638	P41440	Reduced folate transporter	clinvar
SLC24A3	HGNC:10977	ENSG00000185052	Q9HC58	Sodium/potassium/calcium exchanger 3	gwas
SLC7A8	HGNC:11066	ENSG00000092068	Q9UHI5	Large neutral amino acids transporter small subunit 2	clinvar
SOX2	HGNC:11195	ENSG00000181449	P48431	Transcription factor SOX-2	gwas
TALDO1	HGNC:11559	ENSG00000177156	P37837	Transaldolase	clinvar
TNKS	HGNC:11941	ENSG00000173273	O95271	Poly [ADP-ribose] polymerase tankyrase-1	gwas
WRN	HGNC:12791	ENSG00000165392	Q14191	Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN	clinvar
ZNF91	HGNC:13166	ENSG00000167232	Q05481	Zinc finger protein 91	clinvar
DMRTA1	HGNC:13826	ENSG00000176399	Q5VZB9	Doublesex- and mab-3-related transcription factor A1	gwas
CASP7	HGNC:1508	ENSG00000165806	P55210	Caspase-7	gwas
RHBDL3	HGNC:16502	ENSG00000141314	P58872	Rhomboid-related protein 3	gwas
WWP2	HGNC:16804	ENSG00000198373	O00308	NEDD4-like E3 ubiquitin-protein ligase WWP2	gwas
COQ8A	HGNC:16812	ENSG00000163050	Q8NI60	Atypical kinase COQ8A, mitochondrial	gwas
CREB5	HGNC:16844	ENSG00000146592	Q02930	Cyclic AMP-responsive element-binding protein 5	gwas
PLCE1	HGNC:17175	ENSG00000138193	Q9P212	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	gwas
DIRC3	HGNC:17805	ENSG00000231672		disrupted in renal carcinoma 3	gwas
CDKN2B	HGNC:1788	ENSG00000147883	P42772	Cyclin-dependent kinase 4 inhibitor B	gwas
CDKN2C	HGNC:1789	ENSG00000123080	P42773	Cyclin-dependent kinase 4 inhibitor C	gwas
RBFOX1	HGNC:18222	ENSG00000078328	Q9NWB1	RNA binding protein fox-1 homolog 1	gwas
NPLOC4	HGNC:18261	ENSG00000182446	Q8TAT6	Nuclear protein localization protein 4 homolog	gwas
ADGRL2	HGNC:18582	ENSG00000117114	O95490	Adhesion G protein-coupled receptor L2	gwas
MMAA	HGNC:18871	ENSG00000151611	Q8IVH4	Methylmalonic aciduria type A protein, mitochondrial	clinvar
BET1L	HGNC:19348	ENSG00000177951	Q9NYM9	BET1-like protein	gwas
STXBP6	HGNC:19666	ENSG00000168952	Q8NFX7	Syntaxin-binding protein 6	gwas
CIMAP1A	HGNC:19905	ENSG00000177947	Q96PU9	Ciliary microtubule associated protein 1A	gwas
UPF3B	HGNC:20439	ENSG00000125351	Q9BZI7	Regulator of nonsense transcripts 3B	clinvar
QKI	HGNC:21100	ENSG00000112531	Q96PU8	KH domain-containing RNA-binding protein QKI	gwas
RHOT1	HGNC:21168	ENSG00000126858	Q8IXI2	Mitochondrial Rho GTPase 1	gwas
CAPRIN2	HGNC:21259	ENSG00000110888	Q6IMN6	Caprin-2	gwas
TNS3	HGNC:21616	ENSG00000136205	Q68CZ2	Tensin-3	gwas
COL18A1	HGNC:2195	ENSG00000182871	P39060	Collagen alpha-1(XVIII) chain	clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VIM	Vimentin	Vimentins are class-III intermediate filaments found in various non-epithelial cells, especially mesenchymal cells.
PGRMC1	Membrane-associated progesterone receptor component 1	Component of a progesterone-binding protein complex.
RRAGA	Ras-related GTP-binding protein A	Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade.
PANK4	4’-phosphopantetheine phosphatase	Phosphatase which shows a preference for 4’-phosphopantetheine and its oxidatively damaged forms (sulfonate or S-sulfonate), providing strong indirect evidence that the phosphatase activity pre-empts damage in the coenzyme A (CoA) pathway.
AKR1E2	1,5-anhydro-D-fructose reductase	Catalyzes the NADPH-dependent reduction of 1,5-anhydro-D-fructose (AF) to 1,5-anhydro-D-glucitol.
RNLS	Renalase	Catalyzes the oxidation of the less abundant 1,2-dihydro-beta-NAD(P) and 1,6-dihydro-beta-NAD(P) to form beta-NAD(P)(+).
CYP51A1	Lanosterol 14-alpha demethylase	Sterol 14alpha-demethylase that plays a critical role in the cholesterol biosynthesis pathway, being cholesterol the major sterol component in mammalian membranes as well as a precursor for bile acid and steroid hormone synthesis.
TAPT1	Transmembrane anterior posterior transformation protein 1 homolog	Plays a role in primary cilia formation.
FOXE3	Forkhead box protein E3	Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle.
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.
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.
BFSP2	Phakinin	Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA.
BIN3	Bridging integrator 3	Involved in cytokinesis and septation where it has a role in the localization of F-actin.
ATXN7	Ataxin-7	Acts as a component of the SAGA (aka STAGA) transcription coactivator-HAT complex.
BMP3	Bone morphogenetic protein 3	Growth factor of the TGF-beta superfamily that plays an essential role in developmental process by inducing and patterning early skeletal formation and by negatively regulating bone density.
BMP4	Bone morphogenetic protein 4	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis.
SLC19A1	Reduced folate transporter	Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions.
SLC24A3	Sodium/potassium/calcium exchanger 3	Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
SLC7A8	Large neutral amino acids transporter small subunit 2	Associates with SLC3A2 to form a functional heterodimeric complex that translocates small and large neutral amino acids with broad specificity and a stoichiometry of 1:1.
SOX2	Transcription factor SOX-2	Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206.
TALDO1	Transaldolase	Catalyzes the rate-limiting step of the non-oxidative phase in the pentose phosphate pathway.
TNKS	Poly [ADP-ribose] polymerase tankyrase-1	Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking.
WRN	Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN	Multifunctional enzyme that has magnesium and ATP-dependent 3’-5’ DNA-helicase activity on partially duplex substrates.
ZNF91	Zinc finger protein 91	Transcription factor specifically required to repress SINE-VNTR-Alu (SVA) retrotransposons: recognizes and binds SVA sequences and represses their expression by recruiting a repressive complex containing TRIM28/KAP1.
CASP7	Caspase-7	Thiol protease involved in different programmed cell death processes, such as apoptosis, pyroptosis or granzyme-mediated programmed cell death, by proteolytically cleaving target proteins.
RHBDL3	Rhomboid-related protein 3	May be involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.
WWP2	NEDD4-like E3 ubiquitin-protein ligase WWP2	E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
COQ8A	Atypical kinase COQ8A, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
CREB5	Cyclic AMP-responsive element-binding protein 5	Binds to the cAMP response element and activates transcription.
PLCE1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
CDKN2B	Cyclin-dependent kinase 4 inhibitor B	Interacts strongly with CDK4 and CDK6.
CDKN2C	Cyclin-dependent kinase 4 inhibitor C	Interacts strongly with CDK6, weakly with CDK4.
RBFOX1	RNA binding protein fox-1 homolog 1	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.
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.
ADGRL2	Adhesion G protein-coupled receptor L2	Orphan adhesion G-protein coupled receptor (aGPCR), which mediates synapse specificity.
MMAA	Methylmalonic aciduria type A protein, mitochondrial	GTPase, binds and hydrolyzes GTP.
BET1L	BET1-like protein	Vesicle SNARE required for targeting and fusion of retrograde transport vesicles with the Golgi complex.
STXBP6	Syntaxin-binding protein 6	Forms non-fusogenic complexes with SNAP25 and STX1A and may thereby modulate the formation of functional SNARE complexes and exocytosis.
CIMAP1A	Ciliary microtubule associated protein 1A	Outer dense fibers are filamentous structures located on the outside of the axoneme in the midpiece and principal piece of the mammalian sperm tail.
UPF3B	Regulator of nonsense transcripts 3B	Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery.
QKI	KH domain-containing RNA-binding protein QKI	RNA reader protein, which recognizes and binds specific RNAs, thereby regulating RNA metabolic processes, such as pre-mRNA splicing, circular RNA (circRNA) formation, mRNA export, mRNA stability and/or translation.
RHOT1	Mitochondrial Rho GTPase 1	Atypical mitochondrial nucleoside-triphosphatase (NTPase) involved in mitochondrial trafficking.
CAPRIN2	Caprin-2	Promotes phosphorylation of the Wnt coreceptor LRP6, leading to increased activity of the canonical Wnt signaling pathway.
TNS3	Tensin-3	May act as a protein phosphatase and/or a lipid phosphatase.
COL18A1	Collagen alpha-1(XVIII) chain	Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube.
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
THSD7A	Thrombospondin type-1 domain-containing protein 7A	Plays a role in actin cytoskeleton rearrangement.
COPB1	Coatomer subunit beta	The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Go…
VPS13C	Intermembrane lipid transfer protein VPS13C	Mediates the transfer of lipids between membranes at organelle contact sites.
CRYBB3	Beta-crystallin B3	Crystallins are the dominant structural components of the vertebrate eye lens.

Protein-family classification

Druggable: 20 · Difficult: 16 · Unknown: 39 · Druggable fraction: 0.27

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	1	5.2×	0.539
Complement	1	3.6×	0.539
Transporter	3	3.1×	0.539
Phosphatase	2	2.2×	0.539
Scaffold/PPI	7	1.6×	0.539
Enzyme (other)	7	1.1×	0.777
Kinase	3	1.1×	0.777
Transcription factor	9	1.0×	0.777
Other/Unknown	39	0.9×	0.875
GPCR	2	0.6×	0.875
Protease	1	0.5×	0.875

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VIM	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
PGRMC1	Other/Unknown	no		Cyt_B5-like_heme/steroid-bd, Cyt_B5-like_heme/steroid_sf, MAPR/NEUFC/NENF-like
RRAGA	Other/Unknown	no		Gtr1_RagA, P-loop_NTPase, RagA/B
PANK4	Other/Unknown	no		ARMT1-like_metal-bd, Type_II_PanK, PanK_long
AKR1E2	Other/Unknown	no		Aldo/ket_reductase_CS, AKR, NADP_OxRdtase_dom
RNLS	Enzyme (other)	yes	1.6.3.5	Amino_oxidase, FAD/NAD-bd_sf, RNLS
CYP51A1	Enzyme (other)	yes	1.14.13.70	Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CS
MFSD6L	Transporter	yes		MFS_assoc_dom, MFS_trans_sf, MFS_MFSD6
TAPT1	Other/Unknown	no		Tatp1
WDR87	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
FOXE3	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
BFSP2	Other/Unknown	no		Keratin_I, IF_rod_dom
BIN3	Scaffold/PPI	no		BAR_dom, AH/BAR_dom_sf, Bin3_BAR
ATXN7	Other/Unknown	no		SCA7_dom, Ataxin-7-like_regulator
BMP3	Other/Unknown	no		TGF-b_C, TGF-beta-like, BMP3/BMP3B
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
SLC19A1	Transporter	yes		Folate_carrier, SLC19A1, MFS_trans_sf
SLC24A3	Other/Unknown	no		K/Na/Ca-exchanger, NaCa_Exmemb, NCX_ion-bd_dom_sf
SLC7A8	Transporter	yes		AA/rel_permease1, L_AA_transporter, AminoAcid_Transporter
SOX2	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_dom_sf
TALDO1	Other/Unknown	no		TAL/FSA, Transaldolase_1, Aldolase_TIM
TNKS	Scaffold/PPI	no	2.4.2.30	SAM, Ankyrin_rpt, Poly(ADP-ribose)pol_cat_dom
WRN	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, HRDC_dom, 3’-5’_exonuclease_dom
ZNF91	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
DMRTA1	Other/Unknown	no		DM_DNA-bd, DMA, UBA-like_sf
CASP7	Enzyme (other)	yes	3.4.22.60	Pept_C14_p20, Pept_C14_p10, Pept_C14
RHBDL3	Protease	yes		EF_hand_dom, EF-hand-dom_pair, Peptidase_S54_rhomboid_met
WWP2	Scaffold/PPI	no	2.3.2.26	C2_dom, HECT_dom, WW_dom
COQ8A	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom
CREB5	Transcription factor	no		bZIP, Znf_C2H2_type, TF_CRE-BP1-typ
PLCE1	Enzyme (other)	yes	3.1.4.11	C2_dom, RA_dom, PLipase_C_PInositol-sp_X_dom
DIRC3	Other/Unknown	no
CDKN2B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
CDKN2C	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
RBFOX1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
NPLOC4	Transcription factor	no		Znf_RanBP2, NPL4_Zn-bd_put, NPL4_C
ADGRL2	GPCR	yes		GPS, GPCR_2_secretin-like, Lectin_gal-bd_dom
MMAA	Other/Unknown	no		GTPase_ArgK, P-loop_NTPase
BET1L	Other/Unknown	no		T_SNARE_dom, BET1_SNARE
STXBP6	Other/Unknown	no		Sec3-PIP2_bind, STXBP6_PH, STXBP6_SNARE
CIMAP1A	Other/Unknown	no		SHIPPO-rpt, CIMAP
UPF3B	Other/Unknown	no		UPF3_dom, Nucleotide-bd_a/b_plait_sf, UPF3B_RRM-like
QKI	Other/Unknown	no		KH_dom, Quaking_NLS, STAR_dimer
RHOT1	Other/Unknown	no		Small_GTPase, EF_hand_dom, Small_GTP-bd
CAPRIN2	Other/Unknown	no		C1q_dom, Tumour_necrosis_fac-like_dom, Caprin-1_C
TNS3	Phosphatase	yes		Tyr_Pase_dom, SH2, Tyr_Pase_cat
COL18A1	Other/Unknown	no		Collagen, DUF959_COL18_N, Collagenase_NC10/endostatin
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen

Expression context

Cohort genes with no expression data: 0.

64 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	7
male germ line stem cell (sensu Vertebrata) in testis	7
islet of Langerhans	5
endothelial cell	5
right coronary artery	4
adrenal tissue	4
apex of heart	4
blood	4
sperm	4
secondary oocyte	4
lateral nuclear group of thalamus	4
lower esophagus mucosa	4
right adrenal gland	3
left testis	3
oocyte	3
primordial germ cell in gonad	3
upper leg skin	3
jejunal mucosa	3
rectum	3
Brodmann (1909) area 23	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VIM	307	ubiquitous	marker	ventricular zone, descending thoracic aorta, right coronary artery
PGRMC1	301	ubiquitous	marker	seminal vesicle, caput epididymis, adrenal tissue
RRAGA	293	ubiquitous	marker	paraflocculus, frontal pole, Brodmann (1909) area 10
PANK4	134	ubiquitous	yes	apex of heart, right hemisphere of cerebellum, blood
AKR1E2	184	ubiquitous	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium
RNLS	232	ubiquitous	marker	buccal mucosa cell, right adrenal gland, left adrenal gland
CYP51A1	142	ubiquitous	marker	adrenal tissue, ventricular zone, islet of Langerhans
MFSD6L	93	tissue_specific	marker	left testis, sperm, right testis
TAPT1	266	ubiquitous	marker	secondary oocyte, endothelial cell, oocyte
WDR87	27	tissue_specific	marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
FOXE3	36	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon
RHO	38	tissue_specific	marker	optic choroid, neuron projection bundle connecting eye with brain, diaphragm
RORA	284	ubiquitous	marker	upper leg skin, lateral nuclear group of thalamus, skin of hip
BFSP2	111	tissue_specific	yes	lens of camera-type eye, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
BIN3	259	ubiquitous	marker	sural nerve, right adrenal gland cortex, right adrenal gland
ATXN7	290	ubiquitous	marker	mucosa of paranasal sinus, jejunal mucosa, superficial temporal artery
BMP3	126	tissue_specific	marker	muscle layer of sigmoid colon, male germ line stem cell (sensu Vertebrata) in testis, rectum
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum
SLC19A1	238	ubiquitous	marker	jejunal mucosa, blood, endothelial cell
SLC24A3	272	broad	marker	lateral nuclear group of thalamus, tongue squamous epithelium, saphenous vein
SLC7A8	284	ubiquitous	marker	islet of Langerhans, left uterine tube, type B pancreatic cell
SOX2	203	broad	marker	ventricular zone, bronchial epithelial cell, ganglionic eminence
TALDO1	294	ubiquitous	marker	trabecular bone tissue, blood, gingival epithelium
TNKS	295	ubiquitous	yes	middle temporal gyrus, medial globus pallidus, Brodmann (1909) area 23
WRN	252	ubiquitous	marker	calcaneal tendon, sperm, male germ cell
ZNF91	296	ubiquitous	marker	type B pancreatic cell, lateral nuclear group of thalamus, lateral globus pallidus
DMRTA1	131	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, islet of Langerhans
CASP7	269	ubiquitous	marker	rectum, palpebral conjunctiva, epithelium of nasopharynx
RHBDL3	148	broad	marker	right frontal lobe, Brodmann (1909) area 9, right atrium auricular region
WWP2	279	ubiquitous	marker	tibia, tendon of biceps brachii, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 26.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX2	9,645
VIM	6,814
WWP2	4,978
EPHA2	4,794
BMP4	4,425
SIL1	4,196
RHBDL3	3,756
TALDO1	3,738
RHO	3,578
IARS2	3,442

Intra-cohort edges

A	B	Sources
AKR1E2	MFSD6L	string_interaction
AKR1E2	RNLS	string_interaction
AKR1E2	WDR87	string_interaction
BAMBI	BMP4	string_interaction
BET1L	CIMAP1A	string_interaction
BET1L	NPLOC4	string_interaction
BET1L	RIC8A	string_interaction
BFSP2	CRYBB3	string_interaction
BFSP2	FOXE3	string_interaction
BFSP2	WDR87	string_interaction
BMP3	VIM	string_interaction
CDKN2B	DMRTA1	string_interaction
CDKN2C	TENT5C	string_interaction
CIMAP1A	RIC8A	string_interaction
CRYBB3	FOXE3	string_interaction
CRYBB3	WDR87	string_interaction
CYP51A1	PGRMC1	string_interaction
EFNA3	EPHA2	biogrid_interaction, string_interaction
EFNA3	VIM	biogrid_interaction
MFSD6L	RNLS	string_interaction
MFSD6L	TAPT1	string_interaction
MFSD6L	WDR87	string_interaction
QKI	RBFOX1	intact
RNLS	WDR87	string_interaction
SOX2	WWP2	string_interaction
TAPT1	WDR87	string_interaction

Structural data

PDB: 40 · AlphaFold-only: 34 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPHA2	P29317	103
WRN	Q14191	51
ERCC2	P18074	51
CASP7	P55210	47
TNKS	O95271	42
VIM	P08670	26
RRAGA	Q7L523	21
SLC19A1	P41440	19
SOX2	P48431	13
WWP2	O00308	11
CYP51A1	Q16850	10
COL18A1	P39060	9
RHOT1	Q8IXI2	8
CDKN2C	P42773	6
NPLOC4	Q8TAT6	6
ATXN7	O15265	5
CAPRIN2	Q6IMN6	5
TENT5C	Q5VWP2	5
RHO	P08100	4
SLC7A8	Q9UHI5	4
COQ8A	Q8NI60	4
RBFOX1	Q9NWB1	4
SIL1	Q9H173	4
RORA	P35398	3
PLCE1	Q9P212	3
UPF3B	Q9BZI7	3
MMAA	Q8IVH4	2
CFAP299	Q6V702	2
EPM2A	B3EWF7	2
PGRMC1	O00264	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AKR1E2	Q96JD6	93.51
BIN3	Q9NQY0	92.83
RIC8A	Q9NPQ8	90.37
CDKN2B	P42772	90.12
IARS2	Q9NSE4	89.77
BET1L	Q9NYM9	89.02
STXBP6	Q8NFX7	87.31
PANK4	Q9NVE7	87.21
METRNL	Q641Q3	84.20
COPB1	P53618	82.55
PLB1	Q6P1J6	82.18
RHBDL3	P58872	79.68
BMP4	P12644	79.12
BFSP2	Q13515	78.15
CCDC102A	Q96A19	77.35
EFNA3	P52797	74.84
PLEKHH3	Q7Z736	74.53
MFSD6L	Q8IWD5	74.33
CIMAP1A	Q96PU9	74.04
CPAMD8	Q8IZJ3	72.99
HORMAD2	Q8N7B1	72.61
ZNF91	Q05481	72.09
TAPT1	Q6NXT6	71.98
SLC24A3	Q9HC58	70.31
FOXE3	Q13461	66.68
BAMBI	Q13145	64.81
ZNF800	Q2TB10	62.59
CREB5	Q02930	57.95
DMRTA1	Q5VZB9	57.14
CASZ1	Q86V15	53.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 366. Enrichment computed across 99 evidence-associated genes (59 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 59 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TALDO1 deficiency: failed conversion of SH7P, GA3P to Fru(6)P, E4P	1	193.6×	0.166	TALDO1
TALDO1 deficiency: failed conversion of Fru(6)P, E4P to SH7P, GA3P	1	193.6×	0.166	TALDO1
Insulin effects increased synthesis of Xylulose-5-Phosphate	1	96.8×	0.166	TALDO1
Defective MMAA causes MMA, cblA type	1	96.8×	0.166	MMAA
Defective MUT causes MMAM	1	96.8×	0.166	MMAA
XAV939 stabilizes AXIN	1	96.8×	0.166	TNKS
Pentose phosphate pathway disease	1	96.8×	0.166	TALDO1
Diseases of mitochondrial beta oxidation	1	96.8×	0.166	MMAA
Diseases of propionyl-CoA catabolism	1	96.8×	0.166	MMAA
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	2	55.3×	0.166	JAG1, NOTCH1
Caspase-mediated cleavage of cytoskeletal proteins	2	32.3×	0.166	VIM, CASP7
RUNX3 regulates NOTCH signaling	2	27.6×	0.166	JAG1, NOTCH1
Kidney development	2	27.6×	0.166	BMP4, JAG1
Constitutive Signaling by NOTCH1 HD Domain Mutants	2	25.8×	0.166	JAG1, NOTCH1
Germ layer formation at gastrulation	2	22.8×	0.166	BMP4, SOX2
Specification of the neural plate border	2	21.5×	0.166	BMP4, SOX2
NOTCH3 Activation and Transmission of Signal to the Nucleus	2	16.1×	0.166	WWP2, JAG1
Signaling by Retinoic Acid	2	13.8×	0.166	PPARD, RARB
Formation of paraxial mesoderm	2	13.8×	0.166	BMP4, NOTCH1
G1 Phase	2	13.3×	0.166	CDKN2B, CDKN2C
EPHA-mediated growth cone collapse	2	12.9×	0.166	EFNA3, EPHA2
Nuclear Receptor transcription pathway	3	10.2×	0.166	RORA, PPARD, RARB
Metabolism of water-soluble vitamins and cofactors	3	9.2×	0.166	SLC19A1, MMAA, RNLS
Activated NOTCH1 Transmits Signal to the Nucleus	2	12.1×	0.180	JAG1, NOTCH1
Oncogene Induced Senescence	2	11.4×	0.193	CDKN2B, CDKN2C
Inactivation, recovery and regulation of the phototransduction cascade	2	10.8×	0.193	RHO, GUCY2D
Dengue Virus Genome Translation and Replication	2	10.8×	0.193	VIM, NPLOC4
Metabolism of vitamins and cofactors	3	5.9×	0.193	SLC19A1, MMAA, RNLS
R-HSA-197264	1	48.4×	0.203	RNLS
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	48.4×	0.203	JAG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 86 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic hindlimb morphogenesis	4	27.0×	0.013	BMP4, NOTCH1, PITX2, RARB
vascular associated smooth muscle cell differentiation	2	130.6×	0.016	QKI, PITX2
deltoid tuberosity development	2	130.6×	0.016	BMP4, PITX2
distal tubule development	2	130.6×	0.016	JAG1, NOTCH1
inhibition of neuroepithelial cell differentiation	2	98.0×	0.016	JAG1, NOTCH1
ciliary body morphogenesis	2	98.0×	0.016	FOXE3, JAG1
positive regulation of cardiac epithelial to mesenchymal transition	2	98.0×	0.016	JAG1, NOTCH1
pulmonary valve morphogenesis	3	32.7×	0.016	BMP4, JAG1, NOTCH1
negative regulation of stem cell proliferation	3	29.4×	0.016	CDKN2C, PTCH1, RARB
epidermal cell fate specification	2	78.4×	0.019	NOTCH1, PTCH1
regulation of protein import into nucleus	2	78.4×	0.019	BMP4, EPM2A
pericyte cell differentiation	2	78.4×	0.019	BMP4, EPHA2
neuronal stem cell population maintenance	3	23.5×	0.019	SOX2, JAG1, NOTCH1
negative regulation of epithelial cell proliferation	4	13.5×	0.019	BMP4, CDKN2B, NOTCH1, PPARD
negative regulation of myoblast differentiation	3	21.8×	0.022	BMP4, NOTCH1, PPARD
blood vessel endothelial cell proliferation involved in sprouting angiogenesis	2	56.0×	0.030	BMP4, EPHA2
neuroendocrine cell differentiation	2	56.0×	0.030	JAG1, NOTCH1
hair cell differentiation	2	49.0×	0.031	ERCC2, PITX2
positive regulation of epidermal cell differentiation	2	49.0×	0.031	BMP4, PTCH1
male mating behavior	2	49.0×	0.031	DMRTA1, OXT
lens fiber cell development	2	49.0×	0.031	BFSP2, VIM
osteoblast differentiation	5	7.0×	0.031	BMP3, BMP4, SOX2, EPHA2, IGFBP3
visual perception	6	5.5×	0.031	RHO, BFSP2, ATXN7, COL18A1, CRYBB3, GUCY2D
regulation of lamellipodium assembly	2	43.5×	0.035	BIN3, EPHA2
iris morphogenesis	2	43.5×	0.035	FOXE3, PITX2
positive regulation of DNA-templated transcription	10	3.2×	0.036	RORA, ATXN7, BMP4, SOX2, CREB5, CASZ1, BAMBI, NOTCH1 (+2 more)
aortic valve morphogenesis	3	15.1×	0.036	BMP4, JAG1, NOTCH1
in utero embryonic development	6	5.0×	0.043	TENT5C, RIC8A, ERCC2, NOTCH1, PITX2, PTCH1
negative regulation of smooth muscle cell migration	2	35.6×	0.044	IGFBP3, PPARD
positive regulation of endothelial cell differentiation	2	35.6×	0.044	BMP4, NOTCH1

Therapeutics

Drugs indicated for this disease

2 approved, 21 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Diclofenac	Approved (phase 4)
Nepafenac	Approved (phase 4)
Acetohexamide	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)
Bromfenac	Phase 3 (in late-stage trials)
Chloroprocaine	Phase 3 (in late-stage trials)
Clobetasol Propionate	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Dexamethasone Phosphoric Acid	Phase 3 (in late-stage trials)
Difluprednate	Phase 3 (in late-stage trials)
Hydroxocobalamin	Phase 3 (in late-stage trials)
Ketorolac	Phase 3 (in late-stage trials)
Loteprednol Etabonate	Phase 3 (in late-stage trials)
Mapracorat	Phase 3 (in late-stage trials)
Moxifloxacin	Phase 3 (in late-stage trials)
Prednisolone	Phase 3 (in late-stage trials)
Prednisolone Acetate	Phase 3 (in late-stage trials)
Tetracaine	Phase 3 (in late-stage trials)
Tobramycin	Phase 3 (in late-stage trials)
Tromethamine	Phase 3 (in late-stage trials)
Vitamin E	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ciprofloxacin, Citric Acid, Ketamine, Midazolam, Sodium Chloride, Sodium Citrate, Triamcinolone Acetonide.

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 10 · Phased (≥1): 13 · Undrugged: 62

Druggability breadth: 36 of 99 evidence-associated genes (36%) 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
PGRMC1	ENCORAFENIB
CYP51A1	CLOTRIMAZOLE
RORA	TRETINOIN
SLC19A1	PRALATREXATE
TNKS	NIRAPARIB
WRN	INDIGOTINDISULFONATE
CASP7	ACRISORCIN
COQ8A	FEDRATINIB
EPHA2	PONATINIB
ERCC2	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPHA2	50	4
CASP7	32	4
ERCC2	16	4
COQ8A	14	4
CYP51A1	12	4
TNKS	9	4
SLC19A1	4	4
RORA	2	4
WRN	2	4
PGRMC1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENCORAFENIB	4	PGRMC1
CLOTRIMAZOLE	4	CYP51A1
FLUCONAZOLE	4	CYP51A1
KETOCONAZOLE	4	CYP51A1
TERCONAZOLE	4	CYP51A1
BIFONAZOLE	4	CYP51A1
RIFAMPIN	4	CYP51A1
TESTOSTERONE	4	CYP51A1
GRISEOFULVIN	4	CYP51A1
ITRACONAZOLE	4	CYP51A1
ECONAZOLE	4	CYP51A1
MICONAZOLE	4	CYP51A1
TRETINOIN	4	RORA
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	CASP7, SLC19A1
NIRAPARIB	4	TNKS
RUCAPARIB	4	TNKS
TALAZOPARIB	4	TNKS
OLAPARIB	4	TNKS
INDIGOTINDISULFONATE	4	WRN
ACRISORCIN	4	CASP7
CARBOPLATIN	4	CASP7
BITHIONOLATE SODIUM	4	CASP7
RIBOFLAVIN	4	CASP7
DACTINOMYCIN	4	CASP7
TOPOTECAN HYDROCHLORIDE	4	CASP7
FLUPIRTINE	4	CASP7
BITHIONOL	4	CASP7

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 12.

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

Symbol	Assays	Type breakdown
EPHA2	567	Binding:565, Functional:1, ADMET:1
TNKS	226	Binding:223, Functional:3
RORA	115	Binding:111, Functional:3, Unclassified:1
CASP7	107	Binding:99, Functional:8
COQ8A	93	Binding:93
TRIB2	40	Binding:40
WRN	32	Binding:30, Functional:2
CYP51A1	21	Binding:21
VIM	18	Binding:18
SLC19A1	18	Binding:18
COPB1	9	Binding:9
ATXN7	5	Binding:5
PGRMC1	4	Binding:4
SLC7A8	3	Binding:3
ERCC2	3	Binding:3
BMP4	2	Binding:2
IARS2	2	Binding:2
RHO	1	Binding:1
BIN3	1	Binding:1
TALDO1	1	Binding:1
TNS3	1	Binding:1
RIC8A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNLS	1.6.3.5	renalase
CYP51A1	1.14.13.70, 1.14.14.154	sterol 14alpha-demethylase, sterol 14alpha-demethylase
TNKS	2.4.2.30	NAD+ ADP-ribosyltransferase
WRN	3.6.4.12	DNA helicase
CASP7	3.4.22.60	caspase-7
WWP2	2.3.2.26	HECT-type E3 ubiquitin transferase
PLCE1	3.1.4.11	phosphoinositide phospholipase C
TENT5C	2.7.7.19	polynucleotide adenylyltransferase
IARS2	6.1.1.5	isoleucine-tRNA ligase
EPHA2	2.7.10.1	receptor protein-tyrosine kinase
EPM2A	3.1.3.16	protein-serine/threonine phosphatase
ERCC2	3.6.4.12	DNA helicase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RORA	115
TNKS	226
CASP7	107
EPHA2	567

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

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)
ENCORAFENIB	4	PGRMC1
CLOTRIMAZOLE	4	CYP51A1
FLUCONAZOLE	4	CYP51A1
KETOCONAZOLE	4	CYP51A1
TERCONAZOLE	4	CYP51A1
BIFONAZOLE	4	CYP51A1
RIFAMPIN	4	CYP51A1
TESTOSTERONE	4	CYP51A1
GRISEOFULVIN	4	CYP51A1
ITRACONAZOLE	4	CYP51A1
ECONAZOLE	4	CYP51A1
MICONAZOLE	4	CYP51A1
TRETINOIN	4	RORA
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	CASP7, SLC19A1
NIRAPARIB	4	TNKS
RUCAPARIB	4	TNKS
TALAZOPARIB	4	TNKS
OLAPARIB	4	TNKS
INDIGOTINDISULFONATE	4	WRN
ACRISORCIN	4	CASP7
CARBOPLATIN	4	CASP7
BITHIONOLATE SODIUM	4	CASP7
RIBOFLAVIN	4	CASP7
DACTINOMYCIN	4	CASP7
TOPOTECAN HYDROCHLORIDE	4	CASP7
FLUPIRTINE	4	CASP7
BITHIONOL	4	CASP7

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	PGRMC1, CYP51A1, RORA, SLC19A1, TNKS, WRN, CASP7, COQ8A, EPHA2, ERCC2
B	Phased (≥1) drug, not yet approved	3	COPB1, IARS2, TRIB2
C	Druggable family + PDB, no drug	8	RNLS, RHO, SLC7A8, PLCE1, ADGRL2, TNS3, TENT5C, EPM2A
D	Druggable family + AlphaFold only, no drug	3	MFSD6L, RHBDL3, CPAMD8
E	Difficult family or no structure, no drug	51	VIM, RRAGA, PANK4, AKR1E2, TAPT1, WDR87, FOXE3, BFSP2, BIN3, ATXN7 (+41 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EFNA3	0	EPHA2
VIM	18	—
RRAGA	0	—
PANK4	0	—
AKR1E2	0	—
RNLS	0	—
MFSD6L	0	—
TAPT1	0	—
WDR87	0	—
FOXE3	0	—
RHO	1	—
BFSP2	0	—
BIN3	1	—
ATXN7	5	—
BMP3	0	—
BMP4	2	—
SLC24A3	0	—
SLC7A8	3	—
SOX2	0	—
TALDO1	1	—
ZNF91	0	—
DMRTA1	0	—
RHBDL3	0	—
WWP2	0	—
CREB5	0	—
PLCE1	0	—
DIRC3	0	—
CDKN2B	0	—
CDKN2C	0	—
RBFOX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,206.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	827
PHASE4	145
PHASE3	78
PHASE2	21
PHASE1	10
PHASE1/PHASE2	9
PHASE2/PHASE3	5
EARLY_PHASE1	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05157113	PHASE4	RECRUITING	Evaluating a Dropless Postoperative Regimen After Cataract Surgery in a Vulnerable, County-hospital Population
NCT05191706	PHASE4	RECRUITING	Evaluate the Safety of DEXYCU for the Treatment of Inflammation Following Ocular Surgery for Childhood Cataract
NCT06428955	PHASE4	RECRUITING	Evaluation of a Monofocal Intraocular Lens
NCT06922084	PHASE4	RECRUITING	A Prospective, Randomized, Subject and Vision-assessor Masked, Multicenter Study Comparing Bilateral Clareon PanOptix, Bilateral Clareon PanOptix Pro, and Mixed Clareon PanOptix Pro/Vivity Intraocular Lens Implantation in Cataract Subjects
NCT07191847	PHASE4	RECRUITING	Assessment of CataClear, Tear Film Stability, Tear Volume, and Dry Eye Symptoms Using Stem Cells Fortified Eye Drops
NCT07260695	PHASE4	RECRUITING	Odyssey Evaluation in Post LASIK Patients
NCT07301775	PHASE4	NOT_YET_RECRUITING	Comparing Single Versus Multiple Anti-VEGF Injections in Diabetic Patients Undergoing Cataract Surgery
NCT07397949	PHASE4	NOT_YET_RECRUITING	Rebamipide Versus Diquafosol for Perioperative Dry Eye in Cataract Surgery
NCT07471295	PHASE4	NOT_YET_RECRUITING	Toric Performance And Constant Evaluation
NCT00273221	PHASE4	UNKNOWN	Combined Phacotube vs Phacotrabeculectomy:A Randomized Controlled Trial
NCT00312299	PHASE4	COMPLETED	Posterior Capsule Opacification Study
NCT00345046	PHASE4	COMPLETED	A Comparison of Three Different Formulations of Prednisolone Acetate 1%
NCT00347243	PHASE4	COMPLETED	Wavefront Analisys and Contrast Sensitivity of Spherical and Aspherical Intraocular Lenses
NCT00347503	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients
NCT00348244	PHASE4	COMPLETED	Ketorolac vs. Steroid in the Prevention of CME
NCT00348270	PHASE4	COMPLETED	Comparison of the Quality of Vision Provided by AMO Tecnis Z9000 and Alcon Laboratories MA60 Acrysof Posterior Chamber Intraocular Lenses
NCT00348582	PHASE4	COMPLETED	Acular LS vs. Nevanac in Post op Inflammation Following Cataract Surgery
NCT00348621	PHASE4	COMPLETED	A Study of Interventions to Reduce Disability From Visual Loss in Nursing Home Residents
NCT00349583	PHASE4	COMPLETED	Efficacy of Topical Cyclosporine Versus Tears for Improving Visual Outcomes Following Multifocal IOL Implantation
NCT00355446	PHASE4	COMPLETED	Bioavailability of Bimatoprost Ophthalmic Solution in Human Aqueous.
NCT00386438	PHASE4	COMPLETED	Efficacy of Honan Balloon in Intraocular Pressure Reduction Before Phacoemulsification
NCT00392275	PHASE4	COMPLETED	Penetrance of Third Generation Fluoroquinolones in Eyes With Functioning Filtering Blebs
NCT00428363	PHASE4	COMPLETED	Effect of Optic Edge Design in a Silicone Intraocular Lens on Posterior Capsule Opacification
NCT00449267	PHASE4	COMPLETED	Aurolab Hydrophobic Foldable Intraocular Lens Study
NCT00459303	PHASE4	COMPLETED	Comparison of Functional Vision Provided by AMO Tecnis Z9000 and Alcon SA60AT Acrysof
NCT00469690	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients: Trough Drug Effects
NCT00576485	PHASE4	COMPLETED	Spherical Aberration and Contrast Sensitivity in IOLs
NCT00612729	PHASE4	COMPLETED	Light Filters in Intraocular Lenses (IOLs) and Its Influence on Colour and Contrast Vision.
NCT00612781	PHASE4	COMPLETED	Yellow Versus White Study
NCT00630019	PHASE4	COMPLETED	Ocular Tissue Levels of 1.5% Levofloxacin Ophthalmic Solution Compared to an Active Comparator
NCT00673803	PHASE4	COMPLETED	Influence of Two Different Preloaded Intraocular Lens (IOLs) on Posterior Capsule Opacification
NCT00684138	PHASE4	COMPLETED	ACRYSOF® ReSTOR® Aspheric +3.0 D Add Power Intraocular Lens (IOL)
NCT00698724	PHASE4	COMPLETED	Comparing Optical Coherence Tomography (OCT) and Visual Acuity Outcomes in Subjects Undergoing Cataract Surgery, Who Receive Xibrom Ophthalmic Solution and Standard Presurgical Care vs. Xibrom Ophthalmic Solution Plus Prednisolone Acetate 1% and Standard Presurgical Care
NCT00710905	PHASE4	TERMINATED	Visual Function With Contralateral AcrySof® ReSTOR® Aspheric SN6AD1 and SN6AD3
NCT00710931	PHASE4	COMPLETED	Visual Function With Bilateral AcrySof® ReSTOR® Aspheric SN6AD1
NCT00711347	PHASE4	COMPLETED	Intraoperative Floppy Iris Syndrome
NCT00712244	PHASE4	COMPLETED	DisCoVisc Versus DuoVisc, Healon5 and AmVisc Plus
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00719732	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof ReSTOR Aspheric +3
NCT00721253	PHASE4	COMPLETED	Visual Outcomes of Subjects Bilaterally Implanted With ReSTOR Aspheric +4 vs. Tecnis or Acri.LISA

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BROMFENAC	4	26
KETOROLAC	4	23
MOXIFLOXACIN	4	15
NEPAFENAC	4	13
PREDNISOLONE ACETATE	4	11
PREDNISOLONE	4	8
DIQUAFOSOL	4	6
LEVOFLOXACIN ANHYDROUS	4	4
CYCLOPENTOLATE	4	3
DEXMEDETOMIDINE	4	3
TETRACAINE	4	3
TOBRAMYCIN	4	3
TRIAMCINOLONE ACETONIDE	4	3
AFLIBERCEPT	4	2
BESIFLOXACIN	4	2
CLOBETASOL PROPIONATE	4	2
DEXAMETHASONE	4	2
DIFLUPREDNATE	4	2
EPINEPHRINE	4	2
OFLOXACIN	4	2
PHENYLEPHRINE	4	2
VITAMIN E	4	2
ACETIC ACID	4	1
ARTENIMOL	4	1
ASCORBIC ACID	4	1
ATROPINE	4	1
BETA CAROTENE	4	1
BETAMETHASONE	4	1
BEVACIZUMAB	4	1
BIMATOPROST	4	1