Microphthalmia

Summary

Microphthalmia (MONDO:0021129) is a disease (an umbrella term covering 5 Mondo subtypes) caused by variants in GDF6 and VSX2, with 20 cohort genes and 5 clinical trials.

At a glance

• Causal genes: GDF6 (GenCC Definitive), VSX2 (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 20
• ClinVar variants: 101
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microphthalmia
Mondo ID	MONDO:0021129
EFO	EFO:0005569
MeSH	D008850
DOID	DOID:10629
NCIT	C98989
SNOMED CT	204108000
UMLS	C0026010
MedGen	10033
Is cancer (heuristic)	no

Also known as: microphthalmia · microphthalmos · nanophthalmos

Data availability: 101 ClinVar variants · 3 GenCC gene-disease records · 1 HPO phenotype · 1 cell line.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › ocular growth disorder › microphthalmia

Related subtypes (6): pinguecula, myopia, pterygium, keratoconus, Axenfeld-Rieger syndrome, BMP4-related ocular growth disorder

Subtypes (5): isolated microphthalmia, nanophthalmia, syndromic microphthalmia, Kaplowitz-Bodurtha syndrome, microcephaly microphthalmos blindness

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

101 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 16 likely pathogenic, 15 pathogenic, 13 conflicting classifications of pathogenicity, 11 likely benign, 5 pathogenic/likely pathogenic, 2 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267811	46;X;t(X;19)(p22.1;p13.3)dn		Pathogenic	criteria provided, single submitter
1701914	NM_000693.4(ALDH1A3):c.1444del (p.Met482fs)	ALDH1A3	Pathogenic	criteria provided, single submitter
637953	NM_007374.3(SIX6):c.-227_572+235del	C14orf39	Pathogenic	criteria provided, single submitter
1704644	NM_004076.5(CRYBB3):c.467G>A (p.Gly156Glu)	CRYBB3	Pathogenic	criteria provided, single submitter
162153	NM_001347721.2(DYRK1A):c.586C>T (p.Arg196Ter)	DYRK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1710348	NM_003106.4(SOX2):c.103_110dup (p.Ser37fs)	LOC108281177	Pathogenic	criteria provided, single submitter
1173069	NM_005916.5(MCM7):c.776G>C (p.Gly259Ala)	MCM7	Pathogenic	criteria provided, multiple submitters, no conflicts
1804007	NM_005916.5(MCM7):c.133C>T (p.Gln45Ter)	MCM7	Pathogenic	criteria provided, single submitter
430901	NM_001368894.2(PAX6):c.131G>C (p.Arg44Pro)	PAX6	Pathogenic	no assertion criteria provided
1710327	NM_000965.5(RARB):c.654G>C (p.Trp218Cys)	RARB	Pathogenic	criteria provided, single submitter
523459	NM_001372066.1(TFAP2A):c.1043_1044del (p.Lys348fs)	TFAP2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1071776	NM_182894.3(VSX2):c.584G>A (p.Trp195Ter)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387606	NM_182894.3(VSX2):c.371-1G>A	VSX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1406550	NM_182894.3(VSX2):c.598C>T (p.Arg200Ter)	VSX2	Pathogenic	criteria provided, multiple submitters, no conflicts
1430257	NM_182894.3(VSX2):c.589C>T (p.Gln197Ter)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14860	NM_182894.3(VSX2):c.599G>A (p.Arg200Gln)	VSX2	Pathogenic	criteria provided, multiple submitters, no conflicts
14862	NM_182894.3(VSX2):c.679C>T (p.Arg227Trp)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
221963	NM_182894.3(VSX2):c.667G>A (p.Gly223Arg)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4817010	NM_182894.3(VSX2):c.371-2A>C	VSX2	Pathogenic	criteria provided, single submitter
849052	NM_182894.3(VSX2):c.267del (p.Gln90fs)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802998	NM_000693.4(ALDH1A3):c.845G>C (p.Gly282Ala)	ALDH1A3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710337	NM_005267.5(GJA8):c.175C>T (p.Pro59Ser)	GJA8	Likely pathogenic	criteria provided, single submitter
1710325	NM_000965.5(RARB):c.307G>T (p.Gly103Cys)	RARB	Likely pathogenic	criteria provided, single submitter
1710326	NM_000965.5(RARB):c.624_635del (p.Asp208_Arg212delinsGlu)	RARB	Likely pathogenic	criteria provided, single submitter
1710329	NM_000965.5(RARB):c.1205T>C (p.Leu402Pro)	RARB	Likely pathogenic	criteria provided, single submitter
1710342	NM_022369.4(STRA6):c.1699C>T (p.Arg567Ter)	STRA6	Likely pathogenic	criteria provided, single submitter
1710333	NM_001112704.2(VAX1):c.212del (p.Pro71fs)	VAX1	Likely pathogenic	criteria provided, single submitter
3576734	NM_182894.3(VSX2):c.695del (p.Leu232fs)	VSX2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4817006	NM_182894.3(VSX2):c.1059del (p.Pro354fs)	VSX2	Likely pathogenic	criteria provided, single submitter
4817007	NM_182894.3(VSX2):c.1086G>C (p.Ter362Tyr)	VSX2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 49 · 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
GDF6	Definitive	Autosomal dominant	microphthalmia	8
VSX2	Definitive	Autosomal recessive	microphthalmia, isolated, with coloboma 3	8
ZNF219	Limited	Autosomal recessive	microphthalmia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VSX2	Orphanet:98938	Colobomatous microphthalmia
GDF6	Orphanet:2345	Isolated Klippel-Feil syndrome
GDF6	Orphanet:3237	Multiple synostoses syndrome
GDF6	Orphanet:65	Leber congenital amaurosis
GDF6	Orphanet:98938	Colobomatous microphthalmia
TFAP2A	Orphanet:1297	Branchio-oculo-facial syndrome
RAB3GAP2	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP2	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:401830	Autosomal recessive spastic paraplegia type 69
C14orf39	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CILK1	Orphanet:199332	Endocrine-cerebro-osteodysplasia syndrome
CILK1	Orphanet:307	Juvenile myoclonic epilepsy
CRYBB3	Orphanet:98988	Early-onset anterior polar cataract
CRYBB3	Orphanet:98991	Early-onset nuclear cataract
STRA6	Orphanet:2470	Matthew-Wood syndrome
STRA6	Orphanet:98938	Colobomatous microphthalmia
DYRK1A	Orphanet:268261	DYRK1A-related intellectual disability syndrome due to 21q22.13q22.2 microdeletion
DYRK1A	Orphanet:464311	Intellectual disability syndrome due to a DYRK1A point mutation
ALDH1A3	Orphanet:35612	Nanophthalmos
ALDH1A3	Orphanet:98938	Colobomatous microphthalmia
GJA8	Orphanet:1377	Cataract-microcornea syndrome
GJA8	Orphanet:91490	Isolated congenital sclerocornea
GJA8	Orphanet:98984	Pulverulent cataract
GJA8	Orphanet:98985	Early-onset sutural cataract
GJA8	Orphanet:98991	Early-onset nuclear cataract
GJA8	Orphanet:98994	Total early-onset cataract
MCM7	Orphanet:2512	Autosomal recessive primary microcephaly
MIP	Orphanet:441452	Early-onset lamellar cataract
MIP	Orphanet:98985	Early-onset sutural cataract
MIP	Orphanet:98989	Cerulean cataract
MIP	Orphanet:98991	Early-onset nuclear cataract
MIP	Orphanet:98993	Early-onset posterior polar cataract
MIP	Orphanet:98994	Total early-onset cataract
PAX6	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
PAX6	Orphanet:2253	Foveal hypoplasia-presenile cataract syndrome
PAX6	Orphanet:2334	Autosomal dominant keratitis
PAX6	Orphanet:250923	Isolated aniridia
PAX6	Orphanet:35737	Morning glory disc anomaly
PAX6	Orphanet:708	Peters anomaly
PAX6	Orphanet:893	WAGR syndrome
PAX6	Orphanet:98942	Coloboma of choroid and retina
PAX6	Orphanet:98943	Coloboma of eye lens
PAX6	Orphanet:98944	Coloboma of iris
PAX6	Orphanet:98945	Coloboma of macula
PAX6	Orphanet:98946	Coloboma of eyelid
PAX6	Orphanet:98947	Coloboma of optic disc
RARB	Orphanet:689829	Microphthalmia-motor delay-language delay-brain anomalies-diaphragmatic hernia syndrome
RBP4	Orphanet:352718	Progressive retinal dystrophy due to retinol transport defect
RBP4	Orphanet:98938	Colobomatous microphthalmia

Cohort genes → proteins

20 cohort genes, 20 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VSX2	HGNC:1975	ENSG00000119614	P58304	Visual system homeobox 2	gencc,clinvar
ZNF219	HGNC:13011	ENSG00000165804	Q9P2Y4	Zinc finger protein 219	gencc
GDF6	HGNC:4221	ENSG00000156466	Q6KF10	Growth/differentiation factor 6	gencc
TFAP2A	HGNC:11742	ENSG00000137203	P05549	Transcription factor AP-2-alpha	clinvar
VAX1	HGNC:12660	ENSG00000148704	Q5SQQ9	Ventral anterior homeobox 1	clinvar
ZNF91	HGNC:13166	ENSG00000167232	Q05481	Zinc finger protein 91	clinvar
RAB3GAP2	HGNC:17168	ENSG00000118873	Q9H2M9	Rab3 GTPase-activating protein non-catalytic subunit	clinvar
C14orf39	HGNC:19849	ENSG00000179008	Q8N1H7	Protein SIX6OS1	clinvar
CILK1	HGNC:21219	ENSG00000112144	Q9UPZ9	Serine/threonine-protein kinase ICK	clinvar
CRYBB3	HGNC:2400	ENSG00000100053	P26998	Beta-crystallin B3	clinvar
STRA6	HGNC:30650	ENSG00000137868	Q9BX79	Receptor for retinol uptake STRA6	clinvar
DYRK1A	HGNC:3091	ENSG00000157540	Q13627	Dual specificity tyrosine-phosphorylation-regulated kinase 1A	clinvar
ALDH1A3	HGNC:409	ENSG00000184254	P47895	Retinaldehyde dehydrogenase 3	clinvar
GJA8	HGNC:4281	ENSG00000121634	P48165	Gap junction alpha-8 protein	clinvar
TNPO1	HGNC:6401	ENSG00000083312	Q92973	Transportin-1	clinvar
MCM7	HGNC:6950	ENSG00000166508	P33993	DNA replication licensing factor MCM7	clinvar
MIP	HGNC:7103	ENSG00000135517	P30301	Lens fiber major intrinsic protein	clinvar
PAX6	HGNC:8620	ENSG00000007372	P26367	Paired box protein Pax-6	clinvar
RARB	HGNC:9865	ENSG00000077092	P10826	Retinoic acid receptor beta	clinvar
RBP4	HGNC:9922	ENSG00000138207	P02753	Retinol-binding protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VSX2	Visual system homeobox 2	Acts as a transcriptional regulator through binding to DNA at the consensus sequence 5’-[TC]TAATT[AG][AG]-3’ upstream of gene promoters.
ZNF219	Zinc finger protein 219	Transcriptional regulator.
GDF6	Growth/differentiation factor 6	Growth factor that controls proliferation and cellular differentiation in the retina and bone formation.
TFAP2A	Transcription factor AP-2-alpha	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
VAX1	Ventral anterior homeobox 1	Transcription factor that may function in dorsoventral specification of the forebrain.
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.
RAB3GAP2	Rab3 GTPase-activating protein non-catalytic subunit	Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
C14orf39	Protein SIX6OS1	Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination.
CILK1	Serine/threonine-protein kinase ICK	Required for ciliogenesis.
CRYBB3	Beta-crystallin B3	Crystallins are the dominant structural components of the vertebrate eye lens.
STRA6	Receptor for retinol uptake STRA6	Functions as a retinol transporter.
DYRK1A	Dual specificity tyrosine-phosphorylation-regulated kinase 1A	Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities.
ALDH1A3	Retinaldehyde dehydrogenase 3	Catalyzes the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively.
GJA8	Gap junction alpha-8 protein	Structural component of eye lens gap junctions.
TNPO1	Transportin-1	Functions in nuclear protein import as nuclear transport receptor.
MCM7	DNA replication licensing factor MCM7	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.
MIP	Lens fiber major intrinsic protein	Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient.
PAX6	Paired box protein Pax-6	Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas.
RARB	Retinoic acid receptor beta	Receptor for retinoic acid.
RBP4	Retinol-binding protein 4	Retinol-binding protein that mediates retinol transport in blood plasma.

Protein-family classification

Druggable: 4 · Difficult: 6 · Unknown: 10 · Druggable fraction: 0.2

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	19.3×	0.126
Transcription factor	6	2.5×	0.126
Kinase	2	2.8×	0.269
Other/Unknown	10	0.9×	0.825
Enzyme (other)	1	0.6×	0.825

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VSX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
ZNF219	Transcription factor	no		Histamine_H3_rcpt, Znf_C2H2_type, Znf_C2H2_sf
GDF6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
TFAP2A	Transcription factor	no		TF_AP2, TF_AP2_alpha_N, TF_AP2_C
VAX1	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf
ZNF91	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
RAB3GAP2	Other/Unknown	no		Rab3GAP2, RAB3GAP2_C, RAB3GAP_N
C14orf39	Other/Unknown	no		SIX6OS1
CILK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CRYBB3	Other/Unknown	no		Beta/gamma_crystallin, G_crystallin-like, Beta/Gamma-Crystallin
STRA6	Other/Unknown	no		STRA6-like
DYRK1A	Kinase	yes	2.7.12.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ALDH1A3	Enzyme (other)	yes	1.2.1.5	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH
GJA8	Other/Unknown	no		Connexin, Connexin50_C, Connexin_N
TNPO1	Other/Unknown	no		Importin-beta_N, ARM-like, ARM-type_fold
MCM7	Other/Unknown	no		MCM_dom, AAA+_ATPase, MCM7
MIP	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
PAX6	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
RARB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RBP4	Other/Unknown	no		Lipocln_cytosolic_FA-bd_dom, Retinol-bd/Purpurin, Calycin

Expression context

Cohort genes with no expression data: 0.

16 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)	2
broad (>20)	18
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	5
primordial germ cell in gonad	4
palpebral conjunctiva	4
ventricular zone	3
type B pancreatic cell	3
buccal mucosa cell	3
cortical plate	2
placenta	2
lateral nuclear group of thalamus	2
choroid plexus epithelium	2
right lobe of liver	2
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1
gingiva	1
gingival epithelium	1
upper leg skin	1
caudate nucleus	1
nucleus accumbens	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VSX2	11	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, cortical plate
ZNF219	217	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland cortex
GDF6	104	broad	marker	placenta, primordial germ cell in gonad, ventricular zone
TFAP2A	220	ubiquitous	marker	upper leg skin, gingival epithelium, gingiva
VAX1	38	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, caudate nucleus, nucleus accumbens
ZNF91	296	ubiquitous	marker	type B pancreatic cell, lateral nuclear group of thalamus, lateral globus pallidus
RAB3GAP2	295	ubiquitous	marker	choroid plexus epithelium, lateral nuclear group of thalamus, dorsal root ganglion
C14orf39	129	broad	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
CILK1	268	ubiquitous	marker	adrenal tissue, palpebral conjunctiva, cortical plate
CRYBB3	145	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, mucosa of transverse colon
STRA6	128	broad	marker	stromal cell of endometrium, endometrium, placenta
DYRK1A	294	ubiquitous	marker	amniotic fluid, biceps brachii, Brodmann (1909) area 23
ALDH1A3	244	ubiquitous	marker	palpebral conjunctiva, pigmented layer of retina, parietal pleura
GJA8	17	tissue_specific	yes	buccal mucosa cell, frontal pole, paraflocculus
TNPO1	295	ubiquitous	marker	corpus epididymis, caput epididymis, cauda epididymis
MCM7	143	ubiquitous	marker	embryo, ganglionic eminence, ventricular zone
MIP	91	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right lobe of liver
PAX6	201	broad	marker	palpebral conjunctiva, type B pancreatic cell, ventricular zone
RARB	210	ubiquitous	marker	choroid plexus epithelium, palpebral conjunctiva, buccal mucosa cell
RBP4	244	broad	marker	right lobe of liver, liver, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM7	5,413
PAX6	4,971
DYRK1A	4,909
ALDH1A3	4,146
TNPO1	3,147
TFAP2A	2,734
MIP	2,496
RARB	2,185
RAB3GAP2	1,794
CRYBB3	1,718

Intra-cohort edges

A	B	Sources
ALDH1A3	RARB	string_interaction
ALDH1A3	STRA6	string_interaction
CRYBB3	GJA8	string_interaction
GDF6	STRA6	string_interaction
GDF6	VSX2	string_interaction
GJA8	MIP	string_interaction
RBP4	STRA6	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 10 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYRK1A	Q13627	91
MCM7	P33993	28
RBP4	P02753	23
TNPO1	Q92973	21
ALDH1A3	P47895	10
RARB	P10826	9
TFAP2A	P05549	3
PAX6	P26367	2
RAB3GAP2	Q9H2M9	1
CRYBB3	P26998	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MIP	P30301	91.08
STRA6	Q9BX79	78.18
ZNF91	Q05481	72.09
GDF6	Q6KF10	70.88
GJA8	P48165	65.85
VAX1	Q5SQQ9	65.77
VSX2	P58304	61.65
CILK1	Q9UPZ9	61.47
C14orf39	Q8N1H7	58.97
ZNF219	Q9P2Y4	56.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 69. Enrichment computed across 20 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective visual phototransduction due to STRA6 loss of function	2	634.4×	2e-04	STRA6, RBP4
Developmental Lineage of Mammary Stem Cells	2	126.9×	0.004	TFAP2A, ALDH1A3
The canonical retinoid cycle in rods (twilight vision)	2	86.5×	0.005	STRA6, RBP4
Signaling by Retinoic Acid	2	68.0×	0.007	ALDH1A3, RARB
Retinoid metabolism disease events	1	951.7×	0.015	RBP4
Retinoid cycle disease events	1	237.9×	0.032	STRA6
Diseases associated with visual transduction	1	237.9×	0.032	STRA6
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	237.9×	0.032	TFAP2A
Diseases of the neuronal system	1	237.9×	0.032	STRA6
TFAP2 (AP-2) family regulates transcription of cell cycle factors	1	190.3×	0.033	TFAP2A
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	190.3×	0.033	TFAP2A
Activation of anterior HOX genes in hindbrain development during early embryogenesis	2	15.2×	0.042	PAX6, RARB
DNA strand elongation	1	95.2×	0.047	MCM7
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	95.2×	0.047	TFAP2A
Formation of the anterior neural plate	1	86.5×	0.047	PAX6
Activation of the TFAP2 (AP-2) family of transcription factors	1	79.3×	0.047	TFAP2A
Positive Regulation of CDH1 Gene Transcription	1	79.3×	0.047	TFAP2A
Unwinding of DNA	1	73.2×	0.047	MCM7
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	73.2×	0.047	PAX6
Passive transport by Aquaporins	1	73.2×	0.047	MIP
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	63.4×	0.051	TFAP2A
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	1	52.9×	0.052	TNPO1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	52.9×	0.052	TFAP2A
Specification of the neural plate border	1	52.9×	0.052	TFAP2A
Developmental Lineage of Mammary Gland Alveolar Cells	1	52.9×	0.052	ALDH1A3
SUMOylation of transcription factors	1	47.6×	0.054	TFAP2A
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	45.3×	0.054	ALDH1A3
Regulation of gene expression in beta cells	1	43.3×	0.054	PAX6
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	43.3×	0.054	PAX6
RA biosynthesis pathway	1	39.6×	0.057	ALDH1A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lens development in camera-type eye	4	74.9×	5e-05	CRYBB3, GJA8, MIP, PAX6
negative regulation of neuroblast proliferation	3	180.6×	6e-05	VSX2, VAX1, PAX6
retinol transport	2	842.6×	8e-05	STRA6, RBP4
vitamin A import into cell	2	842.6×	8e-05	STRA6, RBP4
gap junction-mediated intercellular transport	2	280.9×	9e-04	GJA8, MIP
neuroblast proliferation	3	55.0×	9e-04	VSX2, VAX1, PAX6
embryonic eye morphogenesis	2	153.2×	0.003	ALDH1A3, RARB
visual perception	4	15.9×	0.003	VSX2, CRYBB3, MIP, PAX6
eyelid development in camera-type eye	2	105.3×	0.004	TFAP2A, STRA6
embryonic digestive tract development	2	99.1×	0.004	STRA6, RARB
retinal metabolic process	2	93.6×	0.005	ALDH1A3, RBP4
positive regulation of chondrocyte differentiation	2	80.2×	0.006	ZNF219, GDF6
astrocyte differentiation	2	76.6×	0.006	VAX1, PAX6
pancreatic A cell development	1	842.6×	0.013	PAX6
optic cup structural organization	1	842.6×	0.013	TFAP2A
nucleus accumbens development	1	842.6×	0.013	ALDH1A3
oligodendrocyte cell fate specification	1	842.6×	0.013	PAX6
forebrain-midbrain boundary formation	1	842.6×	0.013	PAX6
somatic motor neuron fate commitment	1	842.6×	0.013	PAX6
cell migration involved in metanephros development	1	842.6×	0.013	GDF6
positive regulation of behavior	1	842.6×	0.013	STRA6
alveolar primary septum development	1	842.6×	0.013	STRA6
retinol metabolic process	2	49.6×	0.013	ALDH1A3, RBP4
blood vessel development	2	37.5×	0.013	STRA6, PAX6
camera-type eye development	2	35.9×	0.014	VAX1, STRA6
eye development	2	35.1×	0.014	PAX6, RBP4
optic cup morphogenesis involved in camera-type eye development	1	421.3×	0.017	ALDH1A3
optic vesicle morphogenesis	1	421.3×	0.017	TFAP2A
oculomotor nerve formation	1	421.3×	0.017	TFAP2A
negative regulation of heterochromatin formation	1	421.3×	0.017	DYRK1A

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 16

Druggability breadth: 8 of 20 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
CILK1	MOMELOTINIB
DYRK1A	NIRAPARIB
RARB	BEXAROTENE
RBP4	RETINOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DYRK1A	48	4
CILK1	24	4
RARB	18	4
RBP4	3	4
VSX2	0	0
ZNF219	0	0
GDF6	0	0
TFAP2A	0	0
VAX1	0	0
ZNF91	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	CILK1
FEDRATINIB	4	CILK1
PACRITINIB	4	CILK1
ABEMACICLIB	4	CILK1, DYRK1A
NINTEDANIB	4	CILK1
SUNITINIB	4	CILK1, DYRK1A
MIDOSTAURIN	4	CILK1, DYRK1A
NIRAPARIB	4	DYRK1A
RUCAPARIB	4	DYRK1A
AFATINIB	4	DYRK1A
RUXOLITINIB	4	DYRK1A
PALBOCICLIB	4	DYRK1A
BELUMOSUDIL	4	DYRK1A
AFATINIB DIMALEATE	4	DYRK1A
TOVORAFENIB	4	DYRK1A
BEXAROTENE	4	RARB
AMOXICILLIN	4	RARB
ADAPALENE	4	RARB
TOLCAPONE	4	RARB
KETOCONAZOLE	4	RARB
CYCLOSPORINE	4	RARB
TAZAROTENE	4	RARB
TAMIBAROTENE	4	RARB
TRIFAROTENE	4	RARB
TRETINOIN	4	RARB
TROGLITAZONE	4	RARB
TROVAFLOXACIN	4	RARB
ALPROSTADIL	4	RARB
IBUPROFEN	4	RARB
ZAFIRLUKAST	4	RARB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
DYRK1A	866	Binding:855, Functional:7, ADMET:4
RARB	278	Binding:199, Functional:78, ADMET:1
CILK1	119	Binding:119
ALDH1A3	55	Binding:55
RBP4	32	Binding:29, Functional:3
MCM7	9	Binding:9
TNPO1	7	Binding:7
STRA6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DYRK1A	2.7.12.1	dual-specificity kinase
ALDH1A3	1.2.1.5	aldehyde dehydrogenase [NAD(P)+]

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CILK1	119
DYRK1A	866
RARB	278

Pharmacogenomics

Cohort genes with a PharmGKB record: 20; 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)
MOMELOTINIB	4	CILK1
FEDRATINIB	4	CILK1
PACRITINIB	4	CILK1
ABEMACICLIB	4	CILK1, DYRK1A
NINTEDANIB	4	CILK1
SUNITINIB	4	CILK1, DYRK1A
MIDOSTAURIN	4	CILK1, DYRK1A
NIRAPARIB	4	DYRK1A
RUCAPARIB	4	DYRK1A
AFATINIB	4	DYRK1A
RUXOLITINIB	4	DYRK1A
PALBOCICLIB	4	DYRK1A
BELUMOSUDIL	4	DYRK1A
AFATINIB DIMALEATE	4	DYRK1A
TOVORAFENIB	4	DYRK1A
BEXAROTENE	4	RARB
AMOXICILLIN	4	RARB
ADAPALENE	4	RARB
TOLCAPONE	4	RARB
KETOCONAZOLE	4	RARB
CYCLOSPORINE	4	RARB
TAZAROTENE	4	RARB
TAMIBAROTENE	4	RARB
TRIFAROTENE	4	RARB
TRETINOIN	4	RARB
TROGLITAZONE	4	RARB
TROVAFLOXACIN	4	RARB
ALPROSTADIL	4	RARB
IBUPROFEN	4	RARB
ZAFIRLUKAST	4	RARB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	CILK1, DYRK1A, RARB, RBP4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDH1A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	15	VSX2, ZNF219, GDF6, TFAP2A, VAX1, ZNF91, RAB3GAP2, C14orf39, CRYBB3, STRA6 (+5 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STRA6	1	RBP4
VSX2	0	—
ZNF219	0	—
GDF6	0	—
TFAP2A	0	—
VAX1	0	—
ZNF91	0	—
RAB3GAP2	0	—
C14orf39	0	—
CRYBB3	0	—
ALDH1A3	55	—
GJA8	0	—
TNPO1	7	—
MCM7	9	—
MIP	0	—
PAX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01778543	Not specified	RECRUITING	Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)
NCT05954403	Not specified	RECRUITING	National Cohort on Congenital Defects of the Eye
NCT06293560	Not specified	RECRUITING	Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children
NCT03748732	Not specified	UNKNOWN	Extensive Circumferential Partial Thickness Sclerectomy in Nanophthalmic Eyes
NCT04759560	Not specified	UNKNOWN	Biometric Characteristics of the Eye With Microcornea/Microphthalmia and Congenital Cataract Before And After Cataract Extraction