Refractive error

Summary

Refractive error (MONDO:0004892) is a disease (an umbrella term covering 7 Mondo subtypes) with 75 cohort genes (2,199 GWAS associations across 29 studies) and 287 clinical trials. The dominant Reactome pathway is Negative regulation of activity of TFAP2 (AP-2) family transcription factors (3 cohort genes). Top therapeutic interventions include brimonidine, cyclopentolate, and proparacaine.

At a glance

• Umbrella term: 7 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 2,199
• Clinical trials: 287

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	refractive error
Mondo ID	MONDO:0004892
MeSH	D012030
DOID	DOID:9835
SNOMED CT	39021009
UMLS	C0034951
MedGen	20508
Is cancer (heuristic)	no

Data availability: 2,199 GWAS associations (29 studies).

Disease family

An umbrella term covering 7 Mondo subtypes.

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

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Subtypes (7): aniseikonia, presbyopia, myopia, transient refractive change, anisometropia, hyperopia, astigmatism

Genetics & variants

GWAS landscape

2,199 GWAS associations across 29 studies. Top hits map to 39 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs634990	2e-221	LINC02252 - GJD2	T	0.06
rs11602008	3e-181	LRRC4C	A	0.06
rs12193446	4e-107	LAMA2	G	0.42
rs11777176	4e-106	TOX-DT - RNA5SP267	T	0.04
rs524952	1e-104	LINC02252 - GJD2	T	0.24
rs16890057	9e-95	ZMAT4	A	0.04
rs3138137	1e-93	RDH5	A	0.03
rs7744813	3e-72	KCNQ5	C	0.2
rs17400325	1e-69	PDE11A, PDE11A-AS1	T	0.08
rs12965607	1e-66	MYO5B	T	0.04
rs10746463	5e-64	CD55	A	0.03
rs1550094	2e-61	PRSS56	A	0.19
rs61840036	2e-58	FRMPD2	A	0.03
rs178597	3e-58	LMCD1-AS1	T	0.02
rs3138142	2e-57	RDH5	T	0.21
rs1073986	1e-56	DLG2	T	0.02
rs62183808	3e-55	METAP1D	A	0.03
rs10788333	8e-54	CDHR1	A	0.02
rs6534642	9e-54	ANTXR2	T	0.03
rs9857275	3e-53	PXYLP1, ZBTB38	A	0.02
rs7188859	1e-52	RBFOX1	T	0.17
rs1515259	8e-52	METAP2P1 - RNU7-2P	T	0.02
rs72621438	6e-50	TOX-DT - RNA5SP267	G	0.17
rs7028032	8e-49	ADAMTSL1	T	0.02
rs196052	6e-48	CASC15	A	0.02
rs7541594	3e-46	ZC3H11B - SLC30A10	A	0.02
rs1986023	2e-45	NOG - C17orf67	A	0.02
rs3138141	2e-43	RDH5	A	13.8
rs10500355	6e-43	RBFOX1	A	13.73
rs1790165	4e-40	NTM	A	0.02

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90078860	Backman JD	2021	386,786	43,548	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90082846	Backman JD	2021	386,786	43,548	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90079424	Backman JD	2021	46,020	35,830	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083410	Backman JD	2021	46,020	35,830	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90079427	Backman JD	2021	45,986	35,830	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083413	Backman JD	2021	45,986	35,830	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90079428	Backman JD	2021	4,188	77,628	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083414	Backman JD	2021	4,188	77,628	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90079425	Backman JD	2021	4,185	77,665	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083411	Backman JD	2021	4,185	77,665	Exome sequencing and analysis of 454,787 UK Biobank participants.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	3
Tier 3: regulatory	0
Tier 4: intronic/intergenic	44

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	36
intergenic_variant	7
3_prime_UTR_variant	3
missense_variant	3
synonymous_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs634990	15	34713872	T>A,C,G	0.43	intron_variant	LINC02252 - GJD2	2e-221	Tier 4: intronic/intergenic
rs11602008	11	40127755	A>T	0.134	intron_variant	LRRC4C	3e-181	Tier 4: intronic/intergenic
rs12193446	6	129498893	A>G	0.05	intron_variant	LAMA2	4e-107	Tier 4: intronic/intergenic
rs11777176	8	59263770	C>G,T	0.347	intron_variant	TOX-DT - RNA5SP267	4e-106	Tier 4: intronic/intergenic
rs524952	15	34713685	T>A,C	0.05	intron_variant	LINC02252 - GJD2	1e-104	Tier 4: intronic/intergenic
rs16890057	8	40869063	G>A	0.216	intron_variant	ZMAT4	9e-95	Tier 4: intronic/intergenic
rs3138137	12	55723197	C>A,G	0.471	3_prime_UTR_variant	RDH5	1e-93	Tier 2: splice/UTR
rs7744813	6	72933566	C>A,G,T	0.05	intron_variant	KCNQ5	3e-72	Tier 4: intronic/intergenic
rs17400325	2	177701185	T>C	0.031	missense_variant	PDE11A, PDE11A-AS1	1e-69	Tier 1: coding
rs12965607	18	49864655	T>G	0.127	intron_variant	MYO5B	1e-66	Tier 4: intronic/intergenic
rs10746463	1	207337251	G>A,C,T	0.282	intron_variant	CD55	5e-64	Tier 4: intronic/intergenic
rs1550094	2	232520686	G>A,C,T	0.05	missense_variant	PRSS56	2e-61	Tier 1: coding
rs61840036	10	48198248	A>C	0.27	intron_variant	FRMPD2	2e-58	Tier 4: intronic/intergenic
rs178597	3	8155254	C>T	0.419	intron_variant	LMCD1-AS1	3e-58	Tier 4: intronic/intergenic
rs3138142	12	55721801	C>A,T	0.05	synonymous_variant	RDH5	2e-57	Tier 4: intronic/intergenic
rs1073986	11	84927691	T>A,C,G	0.39	intron_variant	DLG2	1e-56	Tier 4: intronic/intergenic
rs62183808	2	172015170	G>A,C,T	0.232	intron_variant	METAP1D	3e-55	Tier 4: intronic/intergenic
rs10788333	10	84200393	C>A,T	0.454	intron_variant	CDHR1	8e-54	Tier 4: intronic/intergenic
rs6534642	4	79907967	T>C,G	0.215	intron_variant	ANTXR2	9e-54	Tier 4: intronic/intergenic
rs9857275	3	141359346	C>A	0.339	intron_variant	PXYLP1, ZBTB38	3e-53	Tier 4: intronic/intergenic
rs7188859	16	7410425	T>C	0.05	intron_variant	RBFOX1	1e-52	Tier 4: intronic/intergenic
rs1515259	2	145935988	T>G	0.442	intergenic_variant	METAP2P1 - RNU7-2P	8e-52	Tier 4: intronic/intergenic
rs72621438	8	59266021	C>G,T	0.05	intron_variant	TOX-DT - RNA5SP267	6e-50	Tier 4: intronic/intergenic
rs7028032	9	18362603	T>C	0.417	intergenic_variant	ADAMTSL1	8e-49	Tier 4: intronic/intergenic
rs196052	6	22056971	T>A,C,G	0.387	intron_variant	CASC15	6e-48	Tier 4: intronic/intergenic
rs7541594	1	219616093	A>G	0.449	intergenic_variant	ZC3H11B - SLC30A10	3e-46	Tier 4: intronic/intergenic
rs1986023	17	56628062	A>C,G,T	0.366	intergenic_variant	NOG - C17orf67	2e-45	Tier 4: intronic/intergenic
rs3138141	12	55721994	C>A,G,T	0.214	3_prime_UTR_variant	RDH5	2e-43	Tier 2: splice/UTR
rs10500355	16	7409346	T>A	0.354	intron_variant	RBFOX1	6e-43	Tier 4: intronic/intergenic
rs1790165	11	132059077	C>A	0.374	intron_variant	NTM	4e-40	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 58 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP2	Orphanet:261295	20p12.3 microdeletion syndrome
BMP2	Orphanet:93396	Brachydactyly type A2
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
SEMA3D	Orphanet:388	Hirschsprung disease
SIX3	Orphanet:220386	Semilobar holoprosencephaly
SIX3	Orphanet:280195	Septopreoptic holoprosencephaly
SIX3	Orphanet:280200	Microform holoprosencephaly
SIX3	Orphanet:485275	Acquired schizencephaly
SIX3	Orphanet:93924	Lobar holoprosencephaly
SIX3	Orphanet:93925	Alobar holoprosencephaly
SIX3	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SIX6	Orphanet:35612	Nanophthalmos
SIX6	Orphanet:435930	Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome
SIX6	Orphanet:98938	Colobomatous microphthalmia
TCF7L2	Orphanet:528084	Non-specific syndromic intellectual disability
TFAP2B	Orphanet:46627	Char syndrome
TFAP2B	Orphanet:466729	Familial patent arterial duct
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
THRB	Orphanet:566243	Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta
TJP2	Orphanet:238475	Familial hypercholanemia
TJP2	Orphanet:480483	Progressive familial intrahepatic cholestasis type 4
TJP2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TNFSF12	Orphanet:696931	Common variable immunodeficiency phenotype due to TWEAK deficiency
ZIC2	Orphanet:220386	Semilobar holoprosencephaly
ZIC2	Orphanet:280195	Septopreoptic holoprosencephaly
ZIC2	Orphanet:280200	Microform holoprosencephaly
ZIC2	Orphanet:93924	Lobar holoprosencephaly
ZIC2	Orphanet:93925	Alobar holoprosencephaly
ZIC2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
CA8	Orphanet:1766	Dysequilibrium syndrome
CACNA1D	Orphanet:324321	Sinoatrial node dysfunction and deafness
CACNA1D	Orphanet:369929	Primary hyperaldosteronism-seizures-neurological abnormalities syndrome
ADAMTSL1	Orphanet:521445	Microcephaly-facial dysmorphism-ocular anomalies-multiple congenital anomalies syndrome
ZEB2	Orphanet:261537	Mowat-Wilson syndrome due to monosomy 2q22
ZEB2	Orphanet:261552	Mowat-Wilson syndrome due to a ZEB2 point mutation
ZEB2	Orphanet:626	Large/giant congenital melanocytic nevus
ARID2	Orphanet:1465	Coffin-Siris syndrome
RCBTB1	Orphanet:99002	Reticular dystrophy of the retinal pigment epithelium
BICC1	Orphanet:730	Autosomal dominant polycystic kidney disease
C14orf39	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
TTC8	Orphanet:110	Bardet-Biedl syndrome
TTC8	Orphanet:791	Retinitis pigmentosa
ANTXR2	Orphanet:2028	Juvenile hyaline fibromatosis
ANTXR2	Orphanet:2176	Infantile systemic hyalinosis

Cohort genes → proteins

75 cohort genes, 73 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNU6-1	HGNC:10227	ENSG00000206625		RNA, U6 small nuclear 1	gwas
RORB	HGNC:10259	ENSG00000198963	Q92753	Nuclear receptor ROR-beta	gwas
BIN3	HGNC:1054	ENSG00000147439	Q9NQY0	Bridging integrator 3	gwas
CCL4	HGNC:10630	ENSG00000275302	P13236	C-C motif chemokine 4	gwas
BMP2	HGNC:1069	ENSG00000125845	P12643	Bone morphogenetic protein 2	gwas
BMP3	HGNC:1070	ENSG00000152785	P12645	Bone morphogenetic protein 3	gwas
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	gwas
SEMA3D	HGNC:10726	ENSG00000153993	O95025	Semaphorin-3D	gwas
SETMAR	HGNC:10762	ENSG00000170364	Q53H47	Histone-lysine N-methyltransferase SETMAR	gwas
SH3GL2	HGNC:10831	ENSG00000107295	Q99962	Endophilin-A1	gwas
ST8SIA1	HGNC:10869	ENSG00000111728	Q92185	Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase	gwas
SIX3	HGNC:10889	ENSG00000138083	O95343	Homeobox protein SIX3	gwas
SIX6	HGNC:10892	ENSG00000184302	O95475	Homeobox protein SIX6	gwas
SLC14A2	HGNC:10919	ENSG00000132874	Q15849	Urea transporter 2	gwas
SNTB1	HGNC:11168	ENSG00000172164	Q13884	Beta-1-syntrophin	gwas
SSR1	HGNC:11323	ENSG00000124783	P43307	Translocon-associated protein subunit alpha	gwas
SYN3	HGNC:11496	ENSG00000185666	O14994	Synapsin-3	gwas
TCF7L2	HGNC:11641	ENSG00000148737	Q9NQB0	Transcription factor 7-like 2	gwas
TFAP2B	HGNC:11743	ENSG00000008196	Q92481	Transcription factor AP-2-beta	gwas
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	gwas
THRB	HGNC:11799	ENSG00000151090	P10828	Thyroid hormone receptor beta	gwas
MPPED2	HGNC:1180	ENSG00000066382	Q15777	Metallophosphoesterase MPPED2	gwas
TJP2	HGNC:11828	ENSG00000119139	Q9UDY2	Tight junction protein 2	gwas
TNFSF12	HGNC:11927	ENSG00000239697	O43508	Tumor necrosis factor ligand superfamily member 12	gwas
USP25	HGNC:12624	ENSG00000155313	Q9UHP3	Ubiquitin carboxyl-terminal hydrolase 25	gwas
VIPR2	HGNC:12695	ENSG00000106018	P41587	Vasoactive intestinal polypeptide receptor 2	gwas
ZIC2	HGNC:12873	ENSG00000043355	O95409	Zinc finger protein ZIC 2	gwas
C4BPA	HGNC:1325	ENSG00000123838	P04003	C4b-binding protein alpha chain	gwas
HIVEP3	HGNC:13561	ENSG00000127124	Q5T1R4	Transcription factor HIVEP3	gwas
CA8	HGNC:1382	ENSG00000178538	P35219	Carbonic anhydrase-related protein	gwas
SCAND3	HGNC:13851	ENSG00000232040	Q6R2W3	SCAN domain-containing protein 3	gwas
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	gwas
CDRT15	HGNC:14395	ENSG00000223510	Q96T59	CMT1A duplicated region transcript 15 protein	gwas
ADAMTSL1	HGNC:14632	ENSG00000178031	Q8N6G6	ADAMTS-like protein 1	gwas
DSCAML1	HGNC:14656	ENSG00000177103	Q8TD84	Cell adhesion molecule DSCAML1	gwas
ZEB2	HGNC:14881	ENSG00000169554	O60315	Zinc finger E-box-binding homeobox 2	gwas
DNAJB12	HGNC:14891	ENSG00000148719	Q9NXW2	DnaJ homolog subfamily B member 12	gwas
DYNLRB2	HGNC:15467	ENSG00000168589	Q8TF09	Dynein light chain roadblock-type 2	gwas
TFAP2D	HGNC:15581	ENSG00000008197	Q7Z6R9	Transcription factor AP-2-delta	gwas
KIRREL1	HGNC:15734	ENSG00000183853	Q96J84	Kin of IRRE-like protein 1	gwas
RALY	HGNC:15921	ENSG00000125970	Q9UKM9	RNA-binding protein Raly	gwas
CD34	HGNC:1662	ENSG00000174059	P28906	Hematopoietic progenitor cell antigen CD34	gwas
AMOTL2	HGNC:17812	ENSG00000114019	Q9Y2J4	Angiomotin-like protein 2	gwas
NTM	HGNC:17941	ENSG00000182667	Q9P121	Neurotrimin	gwas
ARID2	HGNC:18037	ENSG00000189079	Q68CP9	AT-rich interactive domain-containing protein 2	gwas
RBFOX1	HGNC:18222	ENSG00000078328	Q9NWB1	RNA binding protein fox-1 homolog 1	gwas
RCBTB1	HGNC:18243	ENSG00000136144	Q8NDN9	RCC1 and BTB domain-containing protein 1	gwas
ZNF366	HGNC:18316	ENSG00000178175	Q8N895	Zinc finger protein 366	gwas
ST18	HGNC:18695	ENSG00000147488	O60284	Suppression of tumorigenicity 18 protein	gwas
ZKSCAN8P1	HGNC:18777	ENSG00000226314		ZKSCAN8 pseudogene 1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RORB	Nuclear receptor ROR-beta	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
BIN3	Bridging integrator 3	Involved in cytokinesis and septation where it has a role in the localization of F-actin.
CCL4	C-C motif chemokine 4	Monokine with inflammatory and chemokinetic properties.
BMP2	Bone morphogenetic protein 2	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis.
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.
SEMA3D	Semaphorin-3D	Induces the collapse and paralysis of neuronal growth cones.
SETMAR	Histone-lysine N-methyltransferase SETMAR	Protein derived from the fusion of a methylase with the transposase of an Hsmar1 transposon that plays a role in DNA double-strand break repair, stalled replication fork restart and DNA integration.
SH3GL2	Endophilin-A1	Implicated in synaptic vesicle endocytosis.
ST8SIA1	Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase	Catalyzes the addition of sialic acid in alpha 2,8-linkage to the sialic acid moiety of the ganglioside GM3 to form ganglioside GD3; gangliosides are a subfamily of complex glycosphingolipds that contain one or more residues of sialic acid.
SIX3	Homeobox protein SIX3	Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes.
SIX6	Homeobox protein SIX6	May be involved in eye development.
SLC14A2	Urea transporter 2	Mediates the transport of urea driven by a concentration gradient across the cell membrane of the renal inner medullary collecting duct which is critical to the urinary concentrating mechanism.
SNTB1	Beta-1-syntrophin	Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins.
SSR1	Translocon-associated protein subunit alpha	TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins.
SYN3	Synapsin-3	May be involved in the regulation of neurotransmitter release and synaptogenesis.
TCF7L2	Transcription factor 7-like 2	Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner.
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.
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
THRB	Thyroid hormone receptor beta	Nuclear hormone receptor that can act as a repressor or activator of transcription.
MPPED2	Metallophosphoesterase MPPED2	Displays low metallophosphoesterase activity (in vitro).
TJP2	Tight junction protein 2	Plays a role in tight junctions and adherens junctions.
TNFSF12	Tumor necrosis factor ligand superfamily member 12	Binds to FN14 and possibly also to TNRFSF12/APO3.
USP25	Ubiquitin carboxyl-terminal hydrolase 25	Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions in various biological processes including inflammation and immune response.
VIPR2	Vasoactive intestinal polypeptide receptor 2	G protein-coupled receptor activated by the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (ADCYAP1/PACAP).
ZIC2	Zinc finger protein ZIC 2	Acts as a transcriptional activator or repressor.
C4BPA	C4b-binding protein alpha chain	Controls the classical pathway of complement activation.
HIVEP3	Transcription factor HIVEP3	Plays a role of transcription factor; binds to recognition signal sequences (Rss heptamer) for somatic recombination of immunoglobulin and T-cell receptor gene segments; Also binds to the kappa-B motif of gene such as S100A4, involved in c…
CA8	Carbonic anhydrase-related protein	Does not have a carbonic anhydrase catalytic activity.
CACNA1D	Voltage-dependent L-type calcium channel subunit alpha-1D	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
DSCAML1	Cell adhesion molecule DSCAML1	Cell adhesion molecule that plays a role in neuronal self-avoidance.
ZEB2	Zinc finger E-box-binding homeobox 2	Transcriptional inhibitor that binds to DNA sequence 5’-CACCT-3’ in different promoters.
DNAJB12	DnaJ homolog subfamily B member 12	Acts as a co-chaperone with HSPA8/Hsc70; required to promote protein folding and trafficking, prevent aggregation of client proteins, and promote unfolded proteins to endoplasmic reticulum-associated degradation (ERAD) pathway.
DYNLRB2	Dynein light chain roadblock-type 2	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function.
TFAP2D	Transcription factor AP-2-delta	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
KIRREL1	Kin of IRRE-like protein 1	Required for proper function of the glomerular filtration barrier.
RALY	RNA-binding protein Raly	RNA-binding protein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the liver.
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.
AMOTL2	Angiomotin-like protein 2	Regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites.
NTM	Neurotrimin	Neural cell adhesion molecule.
ARID2	AT-rich interactive domain-containing protein 2	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
RBFOX1	RNA binding protein fox-1 homolog 1	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.
RCBTB1	RCC1 and BTB domain-containing protein 1	May be involved in cell cycle regulation by chromatin remodeling.
ZNF366	Zinc finger protein 366	Has transcriptional repression activity.
ST18	Suppression of tumorigenicity 18 protein	Repressor that binds to DNA sequences containing a bipartite element consisting of a direct repeat of the sequence 5’-AAAGTTT-3’ separated by 2-9 nucleotides.
TOX	Thymocyte selection-associated high mobility group box protein TOX	Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis.
GJD2	Gap junction delta-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
NPAS3	Neuronal PAS domain-containing protein 3	May play a broad role in neurogenesis.
BICC1	Protein bicaudal C homolog 1	Putative RNA-binding protein.
C14orf39	Protein SIX6OS1	Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination.

Protein-family classification

Druggable: 19 · Difficult: 18 · Unknown: 38 · Druggable fraction: 0.25

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
Antibody/Immunoglobulin	8	3.1×	0.049
Nuclear receptor	2	10.3×	0.097
Transcription factor	13	1.4×	0.463
Complement	1	3.6×	0.735
Ion channel	1	1.5×	0.960
Scaffold/PPI	5	1.1×	0.960
Transporter	1	1.0×	0.960
Other/Unknown	38	0.9×	0.960
Protease	1	0.5×	0.960
Enzyme (other)	3	0.5×	0.960
Kinase	1	0.4×	0.960
GPCR	1	0.3×	0.960

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNU6-1	Other/Unknown	no
RORB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
BIN3	Scaffold/PPI	no		BAR_dom, AH/BAR_dom_sf, Bin3_BAR
CCL4	Other/Unknown	no		Chemokine_CC_CS, Chemokine_IL8-like_dom, Interleukin_8-like_sf
BMP2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
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
SEMA3D	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
SETMAR	Enzyme (other)	yes	2.1.1.357	SET_dom, Transposase_1, Post-SET_dom
SH3GL2	Scaffold/PPI	no		SH3_domain, BAR_dom, AH/BAR_dom_sf
ST8SIA1	Enzyme (other)	yes	2.4.99.8	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SIX3	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
SIX6	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
SLC14A2	Transporter	yes		Urea_transporter, Ammonium/urea_transptr
SNTB1	Scaffold/PPI	no		PDZ, PH_domain, PH-like_dom_sf
SSR1	Other/Unknown	no		TRAP_alpha
SYN3	Other/Unknown	no		Synapsin, ATP_grasp_subdomain_1, PreATP-grasp_dom_sf
TCF7L2	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF
TFAP2B	Transcription factor	no		TF_AP2, TF_AP2_beta, TF_AP2_C
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
THRB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
MPPED2	Other/Unknown	no		Calcineurin-like_PHP, Calcineurin-like_Pesterase, Metallo-depent_PP-like
TJP2	Scaffold/PPI	no		SH3_domain, PDZ, ZO
TNFSF12	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_Ligand_Superfamily
USP25	Protease	yes		Peptidase_C19_UCH, UIM_dom, UBA-like_sf
VIPR2	GPCR	yes		GPCR_2_secretin-like, GPCR_2_VIP_rcpt, GPCR_2_extracellular_dom
ZIC2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC
C4BPA	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, C4bp_oligo
HIVEP3	Transcription factor	no		Znf_C2H2_type, Znf_CCHC_HIVEP, Znf_C2H2_sf
CA8	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
SCAND3	Transcription factor	no		Integrase_cat-core, SCAN_dom, RNaseH-like_sf
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu
CDRT15	Other/Unknown	no
ADAMTSL1	Antibody/Immunoglobulin	yes		TSP1_rpt, Ig_sub2, Ig_sub
DSCAML1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ZEB2	Transcription factor	no		HD, Di19_Zn-bd, Homeodomain-like_sf
DNAJB12	Other/Unknown	no		DnaJ_domain, DUF1977_DnaJ-like, DnaJ_domain_CS
DYNLRB2	Other/Unknown	no		Roadblock/LAMTOR2_dom, DYNLRB1/2
TFAP2D	Transcription factor	no		TF_AP2, TF_AP2_C
KIRREL1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
RALY	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, hnRNP_C
CD34	Other/Unknown	no		CD34, CD34/Podocalyxin
AMOTL2	Other/Unknown	no		Angiomotin, Angiomotin_C, Angiomotin-like
NTM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
ARID2	Transcription factor	no		ARID_dom, DNA-bd_RFX, Znf_C2H2_type
RBFOX1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
RCBTB1	Other/Unknown	no		BTB/POZ_dom, Reg_chr_condens, RCC1/BLIP-II
ZNF366	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, C2H2-ZF_domain-containing
ST18	Transcription factor	no		Znf_C2H2C, Myelin_TF, Znf_C2H2C_sf
ZKSCAN8P1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	9
cortical plate	7
sural nerve	6
Brodmann (1909) area 23	6
endothelial cell	6
ventricular zone	6
primordial germ cell in gonad	6
calcaneal tendon	6
corpus callosum	5
middle temporal gyrus	5
buccal mucosa cell	5
pigmented layer of retina	4
ganglionic eminence	4
left testis	4
stromal cell of endometrium	4
adrenal tissue	3
right adrenal gland	3
right adrenal gland cortex	3
pancreatic ductal cell	3
tibia	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNU6-1	117	broad	yes	sural nerve, adrenal tissue, corpus callosum
RORB	196	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
BIN3	259	ubiquitous	marker	sural nerve, right adrenal gland cortex, right adrenal gland
CCL4	131	tissue_specific	marker	granulocyte, spleen, bone marrow
BMP2	238	broad	marker	cartilage tissue, pancreatic ductal cell, pigmented layer of retina
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
SEMA3D	183	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, spleen
SETMAR	250	ubiquitous	marker	body of uterus, popliteal artery, tibial artery
SH3GL2	193	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, endothelial cell
ST8SIA1	224	broad	marker	ventricular zone, ganglionic eminence, cortical plate
SIX3	92	broad	marker	pigmented layer of retina, retina, nasal cavity epithelium
SIX6	34	tissue_specific	marker	adenohypophysis, pituitary gland, cranial nerve II
SLC14A2	100	tissue_specific	marker	primordial germ cell in gonad, hair follicle, right adrenal gland
SNTB1	245	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
SSR1	302	ubiquitous	marker	corpus epididymis, caput epididymis, trabecular bone tissue
SYN3	176	broad	marker	primordial germ cell in gonad, cortical plate, primary visual cortex
TCF7L2	291	ubiquitous	marker	lateral nuclear group of thalamus, endothelial cell, pancreatic ductal cell
TFAP2B	128	broad	marker	corpus epididymis, cauda epididymis, oocyte
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
THRB	267	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, tibia
MPPED2	255	broad	marker	ventricular zone, ganglionic eminence, cortical plate
TJP2	134	ubiquitous	marker	corpus callosum, descending thoracic aorta, thoracic aorta
TNFSF12	134	tissue_specific	marker	right coronary artery, thoracic aorta, ascending aorta
USP25	285	ubiquitous	marker	sperm, male germ cell, skeletal muscle tissue of rectus abdominis
VIPR2	169	broad	marker	mucosa of stomach, apex of heart, heart left ventricle
ZIC2	139	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
C4BPA	166	tissue_specific	marker	right lobe of liver, liver, lower lobe of lung
HIVEP3	234	ubiquitous	marker	buccal mucosa cell, endothelial cell, Brodmann (1909) area 23
CA8	184	broad	marker	metanephros cortex, right hemisphere of cerebellum, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD34	4,928
TGFBR1	4,828
BMP4	4,425
CLU	4,205
TCF7L2	3,775
PNPT1	3,741
RALY	3,651
ZEB2	3,193
BMP2	3,131
COL6A1	3,049

Intra-cohort edges

A	B	Sources
ANTXR2	LRFN5	string_interaction
ANTXR2	TJP2	string_interaction
BMP4	SIX6	string_interaction
CACNA1D	SNTB1	intact
CAGE1	MPPED2	biogrid_interaction, intact
GJD2	TJP2	intact, string_interaction
KCTD15	TFAP2B	string_interaction
LRFN5	TJP2	string_interaction
LYPLAL1	TFAP2B	string_interaction
NPAS3	RBFOX1	string_interaction
SIX3	SIX6	biogrid_interaction, intact
SIX3	ZIC2	string_interaction
TFAP2B	TFAP2D	biogrid_interaction

Structural data

PDB: 42 · AlphaFold-only: 31 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBR1	P36897	44
THRB	P10828	34
GJD2	Q9UKL4	24
BMP2	P12643	21
ANTXR2	P58335	14
PNPT1	Q8TCS8	11
SLC14A2	Q15849	9
C4BPA	P04003	9
L3MBTL3	Q96JM7	9
CCL4	P13236	8
USP25	Q9UHP3	7
CACNA1D	Q01668	6
SETMAR	Q53H47	5
SH3GL2	Q99962	4
RBFOX1	Q9NWB1	4
LRFN5	Q96NI6	4
SSR1	P43307	3
TCF7L2	Q9NQB0	3
VIPR2	P41587	3
BICC1	Q9H694	3
SNTB1	Q13884	2
TJP2	Q9UDY2	2
NTM	Q9P121	2
ARID2	Q68CP9	2
LYPLAL1	Q5VWZ2	2
CLU	P10909	2
KCTD15	Q96SI1	2
BMP3	P12645	1
SYN3	O14994	1
TFAP2B	Q92481	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPPED2	Q15777	95.43
RCBTB1	Q8NDN9	92.98
BIN3	Q9NQY0	92.83
ST8SIA1	Q92185	88.71
TRAM1	Q15629	84.56
TTC8	Q8TAM2	84.48
SEMA3D	O95025	84.10
SIX6	O95475	81.68
RORB	Q92753	79.48
BMP4	P12644	79.12
LRMDA	Q9H2I8	78.40
GALNT15	Q8N3T1	77.98
LRIT2	A6NDA9	77.76
KIRREL1	Q96J84	75.58
LRIT1	Q9P2V4	73.66
SCAND3	Q6R2W3	72.39
ADAMTSL1	Q8N6G6	71.26
SIX3	O95343	70.38
AMOTL2	Q9Y2J4	67.35
CAGE1	Q8TC20	63.17
TFAP2D	Q7Z6R9	62.75
CD34	P28906	60.99
TMC3	Q7Z5M5	59.93
C14orf39	Q8N1H7	58.97
ZNF366	Q8N895	57.54
NPAS3	Q8IXF0	56.50
TOX	O94900	54.57
CDRT15	Q96T59	52.21
ZIC2	O95409	51.36
LINC00862	A6NCI5	50.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 491. Enrichment computed across 173 evidence-associated genes (96 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 96 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	3	35.7×	0.033	TFAP2B, TFAP2D, KCTD15
cGMP effects	3	22.3×	0.033	KCNMA1, PDE10A, PDE11A
Molecules associated with elastic fibres	4	12.9×	0.033	BMP2, BMP4, EFEMP1, FBN1
Expression of BMAL (ARNTL), CLOCK, and NPAS2	4	12.2×	0.033	RORB, NCOA2, NRIP1, MED1
G alpha (s) signalling events	7	5.3×	0.033	VIPR2, DRD1, FSHB, GNB3, PDE10A, PDE11A, PDE3A
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	3	19.8×	0.035	TFAP2B, TFAP2D, KCTD15
Signaling by ALK	3	17.8×	0.041	ALKAL2, ALKAL1, MYCN
Potassium Channels	5	7.0×	0.045	KCNA4, KCNJ2, KCNJ5, KCNMA1, KCNQ5
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	3	12.8×	0.080	NCOA2, NRIP1, MED1
Activation of G protein gated Potassium channels	3	12.3×	0.080	GNB3, KCNJ2, KCNJ5
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	3	12.3×	0.080	GNB3, KCNJ2, KCNJ5
Signaling by TGFBR3	3	11.5×	0.089	TGFBR1, APH1B, MYCN
Signaling by Receptor Tyrosine Kinases	7	3.8×	0.097	SH3GL2, APH1B, ALKAL2, ALKAL1, LAMA2, AREG, MYCN
G protein gated Potassium channels	2	23.8×	0.099	KCNJ2, KCNJ5
Elastic fibre formation	3	10.5×	0.099	BMP2, BMP4, FBN1
GABA receptor activation	3	9.9×	0.103	GABRR1, KCNJ2, KCNJ5
Formation of the anterior neural plate	2	21.6×	0.106	ZIC2, ZEB2
Activation of the TFAP2 (AP-2) family of transcription factors	2	19.8×	0.119	TFAP2B, TFAP2D
Signaling by LTK	2	18.3×	0.133	ALKAL2, ALKAL1
Defective EXT2 causes exostoses 2	2	17.0×	0.133	GPC5, GPC6
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	2	17.0×	0.133	GPC5, GPC6
Gastrulation	3	8.1×	0.133	BMP4, TCF7L2, TFAP2B
Inwardly rectifying K+ channels	2	14.9×	0.158	KCNJ2, KCNJ5
R-HSA-1368082	2	14.9×	0.158	NCOA2, MED1
Regulation of Complement cascade	3	7.3×	0.158	C4BPA, CLU, CD55
Specification of the neural plate border	2	13.2×	0.162	BMP4, TFAP2B
Attachment and Entry	2	12.5×	0.162	GPC5, GPC6
Activation of GABAB receptors	2	12.5×	0.162	KCNJ2, KCNJ5
Defective B4GALT7 causes EDS, progeroid type	2	11.9×	0.162	GPC5, GPC6
Defective B3GAT3 causes JDSSDHD	2	11.9×	0.162	GPC5, GPC6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 146 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telencephalon regionalization	3	57.7×	0.014	BMP2, BMP4, SIX3
positive regulation of epithelial cell proliferation	6	10.0×	0.017	BMP4, ST8SIA1, TCF7L2, SCAND3, MYCN, NOG
positive regulation of ERK5 cascade	2	115.4×	0.028	ALKAL2, ALKAL1
post-embryonic eye morphogenesis	2	77.0×	0.049	EFEMP1, FBN1
thyroid hormone receptor signaling pathway	2	57.7×	0.049	THRB, MED1
lens induction in camera-type eye	2	57.7×	0.049	BMP4, SIX3
prostatic bud formation	2	57.7×	0.049	BMP4, NOG
regulation of hormone metabolic process	2	46.2×	0.049	TCF7L2, GNB3
myofibroblast differentiation	2	46.2×	0.049	TGFBR1, ZEB2
positive regulation of odontogenesis	2	46.2×	0.049	BMP2, CD34
negative regulation of complement activation	2	46.2×	0.049	CLU, CD55
lung morphogenesis	3	21.6×	0.049	BMP4, COL6A1, NOG
telencephalon development	3	20.4×	0.049	BMP2, BMP4, SIX3
glutamate receptor signaling pathway	3	19.2×	0.049	GRIA4, GRIK1, GRIN2B
synaptic transmission, glutamatergic	4	9.8×	0.049	DRD1, GRIA4, GRIK1, GRIN2B
camera-type eye development	4	9.8×	0.049	EFEMP1, FBN1, PRSS56, GPD2
visual perception	8	4.4×	0.049	RORB, SIX3, SIX6, ZIC2, GJD2, LRIT1, EFEMP1, RDH5
negative regulation of receptor guanylyl cyclase signaling pathway	2	38.5×	0.056	PDE10A, PDE11A
mammary gland branching involved in thelarche	2	38.5×	0.056	AREG, MED1
epithelial cell proliferation involved in mammary gland duct elongation	2	38.5×	0.056	AREG, MED1
mRNA transcription by RNA polymerase II	4	9.1×	0.056	THRB, NCOA2, POLR2A, MED1
positive regulation of epithelial to mesenchymal transition	4	8.7×	0.056	BMP2, BMP4, TCF7L2, TGFBR1
skeletal system development	6	5.2×	0.056	BMP2, BMP3, TGFBR1, COL10A1, FBN1, NOG
negative regulation of chondrocyte differentiation	3	13.8×	0.058	BMP4, TGFBR1, EFEMP1
regulation of neuronal synaptic plasticity	3	13.8×	0.058	GRIN2B, NOG, RASGRF1
ventricular compact myocardium morphogenesis	2	33.0×	0.060	TGFBR1, NOG
regulation of odontogenesis of dentin-containing tooth	2	33.0×	0.060	BMP2, BMP4
positive regulation of odontoblast differentiation	2	33.0×	0.060	BMP2, BMP4
pituitary gland development	3	13.3×	0.060	BMP4, SIX3, NOG
heart induction	2	28.9×	0.064	BMP2, BMP4

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Carboxymethylcellulose Sodium, Glycerin, Riboflavin.

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 68

Druggability breadth: 57 of 173 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RORB	TRETINOIN
TGFBR1	MOMELOTINIB
THRB	AMINOCAPROIC ACID
CACNA1D	BEPRIDIL
L3MBTL3	CHLORPHENIRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THRB	117	4
CACNA1D	48	4
TGFBR1	28	4
RORB	2	4
VIPR2	2	3
SSR1	1	2
L3MBTL3	1	4
RNU6-1	0	0
BIN3	0	0
CCL4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORB
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	TGFBR1
DASATINIB	4	CACNA1D, TGFBR1
CRIZOTINIB	4	TGFBR1
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
AMILORIDE HYDROCHLORIDE	4	THRB
ALTRETAMINE	4	THRB
BISOPROLOL FUMARATE	4	THRB
ATORVASTATIN	4	THRB
OXYTETRACYCLINE	4	THRB
LIOTHYRONINE	4	THRB
MECLOFENAMATE SODIUM	4	THRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
CACNA1D	233	Binding:145, Functional:81, Toxicity:5, ADMET:2
THRB	169	Binding:129, Functional:40
RORB	90	Binding:87, Functional:3
L3MBTL3	50	Binding:49, Functional:1
VIPR2	27	Functional:14, Binding:13
BMP2	22	Binding:18, Functional:4
TCF7L2	22	Binding:22
USP25	19	Binding:19
SSR1	7	Binding:7
ARID2	7	Binding:7
ANTXR2	3	Binding:3
BMP4	2	Binding:2
LYPLAL1	2	Binding:2
BIN3	1	Binding:1
SETMAR	1	Binding:1
DNAJB12	1	Binding:1
TRAM1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SETMAR	2.1.1.357, 2.7.7.B22	[histone H3]-lysine36 N-dimethyltransferase,
ST8SIA1	2.4.99.8	alpha-N-acetylneuraminate alpha-2,8-sialyltransferase
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
CA8	4.2.1.1	carbonic anhydrase
PNPT1	2.7.7.8	polyribonucleotide nucleotidyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TGFBR1	541
THRB	169
CACNA1D	233

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)
TRETINOIN	4	RORB
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1
NINTEDANIB	4	TGFBR1
DASATINIB	4	CACNA1D, TGFBR1
CRIZOTINIB	4	TGFBR1
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
AMILORIDE HYDROCHLORIDE	4	THRB
ALTRETAMINE	4	THRB
BISOPROLOL FUMARATE	4	THRB
ATORVASTATIN	4	THRB
OXYTETRACYCLINE	4	THRB
LIOTHYRONINE	4	THRB
MECLOFENAMATE SODIUM	4	THRB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	RORB, TGFBR1, THRB, CACNA1D, L3MBTL3
B	Phased (≥1) drug, not yet approved	2	SSR1, VIPR2
C	Druggable family + PDB, no drug	8	SETMAR, SLC14A2, USP25, C4BPA, CA8, DSCAML1, NTM, LRFN5
D	Druggable family + AlphaFold only, no drug	6	SEMA3D, ST8SIA1, ADAMTSL1, KIRREL1, LRIT1, LRIT2
E	Difficult family or no structure, no drug	54	RNU6-1, BIN3, CCL4, BMP2, BMP3, BMP4, SH3GL2, SIX3, SIX6, SNTB1 (+44 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNU6-1	0	—
BIN3	1	—
CCL4	0	—
BMP2	22	—
BMP3	0	—
BMP4	2	—
SEMA3D	0	—
SETMAR	1	—
SH3GL2	0	—
ST8SIA1	0	—
SIX3	0	—
SIX6	0	—
SLC14A2	0	—
SNTB1	0	—
SYN3	0	—
TCF7L2	22	—
TFAP2B	0	—
MPPED2	0	—
TJP2	0	—
TNFSF12	0	—
USP25	19	—
ZIC2	0	—
C4BPA	0	—
HIVEP3	0	—
CA8	0	—
SCAND3	0	—
CDRT15	0	—
ADAMTSL1	0	—
DSCAML1	0	—
ZEB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 287.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	265
PHASE3	8
PHASE4	6
PHASE2	5
PHASE1	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00348621	PHASE4	COMPLETED	A Study of Interventions to Reduce Disability From Visual Loss in Nursing Home Residents
NCT01250925	PHASE4	COMPLETED	Effect of Contact Lens Wear on Immune Cell Density and Morphology of the Ocular Surface
NCT02177539	PHASE4	UNKNOWN	A New More Efficient Cycloplegia Scheme
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT05449015	PHASE4	UNKNOWN	Study on the Effect of Two Ways of Cycloplegia on Biological Parameters of Ciliary Muscle
NCT06077682	PHASE4	UNKNOWN	Cycloplegic Refraction in Pediatric Patients With Esotropia
NCT00038753	PHASE3	UNKNOWN	Vision In Preschoolers Study (VIP Study)
NCT00317525	PHASE3	COMPLETED	Effects of Different Add Powers on the Comfort and Productivity of Computer Users With Fixed or Free Head Movement
NCT00318045	PHASE3	UNKNOWN	Effects of Optical Blur on Performance and Comfort of Computer Users
NCT00585026	PHASE3	TERMINATED	Randomized Clinical Trial of Bifocal Lenses Versus Computer-specific Progressive Addition Lenses
NCT01322919	PHASE3	COMPLETED	Safety and Efficacy Study to Evaluate the Treatment of Both Near and Distance Vision in a Simultaneous Laser Procedure
NCT04465279	PHASE2/PHASE3	COMPLETED	Trifocal Diffractive Intraocular Lens After Cataract Extraction With Phacoemulsification
NCT05656027	PHASE3	COMPLETED	Phase 3 Evaluation of the Safety and Efficacy of LNZ100 & LNZ101 for the Treatment of Presbyopia
NCT05728944	PHASE3	COMPLETED	Phase 3 Efficacy Study of LNZ100 & LNZ101 for the Treatment of Presbyopia
NCT05753189	PHASE3	COMPLETED	Phase 3 Safety Study of LNZ100 and LNZ101 for the Treatment of Presbyopia Subjects
NCT00918697	PHASE2	COMPLETED	Mechanical Versus Alcohol Epithelial Debridement During Hotorefractive Keratectomy (PRK)
NCT03552016	PHASE2	SUSPENDED	Evaluation of Progression of Myopia in Children Treated With Vitamin B2 and Outdoor Sunlight Exposure
NCT05059041	PHASE2	COMPLETED	Dilated Versus Non-Dilated Wavefront Corrections for Patients With Down Syndrome
NCT05294328	PHASE2	COMPLETED	Evaluation of the Safety and Effectiveness of Aceclidine/Brimonidine (LNZ101) and Aceclidine (LNZ100) in the Treatment of Presbyopia
NCT05431543	PHASE2	COMPLETED	Evaluation of the Safety and Effectiveness of Aceclidine (LNZ101) and Aceclidine + Brimonidine (LNZ100) in the Treatment of Presbyopia
NCT01122004	PHASE1	UNKNOWN	The Effect of Gabapentin (Neurentin) and Pregabalin (Lyrica) in Pain Reduction After Photorefractive Keratectomy
NCT05936489	PHASE1	COMPLETED	Plasma Pharmacokinetics and Safety of LNZ101 and LNZ100 Ophthalmic Solutions in Healthy Adult Subjects With Presbyopia
NCT03030755	Not specified	RECRUITING	Corneal Elastography and Patient Specific Modeling
NCT04077086	Not specified	RECRUITING	Correcting Myopia Among Secondary School Children to Increase Academic High School Attendance Rates in Rural Communities
NCT04632784	Not specified	ACTIVE_NOT_RECRUITING	Clinical Trial With Artiflex Presbyopic (Artiplus)
NCT04740593	Not specified	ACTIVE_NOT_RECRUITING	The Effect of Early Glasses on the Development of Amblyopia
NCT05458323	Not specified	RECRUITING	Cognitive Level Enhancement Through Vision Exams and Refraction
NCT05550740	Not specified	ACTIVE_NOT_RECRUITING	Repeated Low-Level Red-Light Therapy for Shortening Axial Length
NCT05670626	Not specified	ENROLLING_BY_INVITATION	Correlation Between Preoperative Refraction and Anterior Segment Parameters With ICL Vault
NCT05733182	Not specified	RECRUITING	Effect of Colour Temperature of Reading Lamp on Refractive Error Development
NCT05856786	Not specified	RECRUITING	To Study the Effects of Refractive Surgery on OCT Measurements in the Eye
NCT06565091	Not specified	RECRUITING	Clinical Investigation for a Multifunction Ophthalmic Measurement Device
NCT06849895	Not specified	NOT_YET_RECRUITING	Real-World Study of Myopia Prevention and Control in Children
NCT06913491	Not specified	ACTIVE_NOT_RECRUITING	Efficacy of PEEK Acuity Versus ETDRS Chart for Assessment of Visual Acuity and Refractive Error
NCT06996353	Not specified	RECRUITING	Clinical Data Collection of Myopic Patients After PTK-PRK With CZM MEL 90 Excimer Laser
NCT07001124	Not specified	ACTIVE_NOT_RECRUITING	Comparative Efficacy of Duochrome Test Verse +1 Blur Test in Detecting Refracting Error Across Different Ages
NCT07036835	Not specified	ACTIVE_NOT_RECRUITING	Clinical Investigation of a Femtosecond Laser for Corneal Flap Creation
NCT07168564	Not specified	RECRUITING	Post Marketing Clinical Study on the Efficacy of Lenses From a New Prescription Protocol
NCT07240480	Not specified	NOT_YET_RECRUITING	Assessing the Turkish DDIVAT for Visual Acuity Measurement
NCT07241806	Not specified	NOT_YET_RECRUITING	Measurment of Optic Disc Parameters, RNFL Thickness and Ganglion Cell Complex in Myopic, Hypermetropic and Emmetropic Patients Using OCT and Axial Length Measurments

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BRIMONIDINE	4	8
CYCLOPENTOLATE	4	2
PROPARACAINE	4	2
TROPICAMIDE	4	2
BENOXINATE	4	1
HYDROGEN PEROXIDE	4	1
PHENYLEPHRINE	4	1
RIBOFLAVIN	4	1
TOBRAMYCIN	4	1
ACECLIDINE	3	6
ETAFILCON A	3	6
SENOFILCON A	3	4
COMFILCON A	3	2
NELFILCON A	3	2
ASTAXANTHIN	3	1
ENFILCON A	3	1
GALYFILCON A	3	1
LOTRAFILCON B	3	1
MAXACALCITOL	3	1
OCUFILCON D	3	1
BALAFILCON A	1	1
CHEMBL1457550	0	2
CHEMBL511565	0	1
CHEMBL5267279	0	1
CHEMBL4127074	0	1
CHEMBL1358053	0	1
HEFILCON A	-1	1
NESOFILCON A	-1	1