Isolated microphthalmia 2

Summary

Isolated microphthalmia 2 (MONDO:0012409) is a disease caused by VSX2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: VSX2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 385

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated microphthalmia 2
Mondo ID	MONDO:0012409
MeSH	C566446
OMIM	610093
DOID	DOID:0060839
UMLS	C1864720
MedGen	351204
GARD	0024863
Is cancer (heuristic)	no

Also known as: isolated microphthalmia caused by mutation in VSX2 · isolated microphthalmia type 2 · MCOP2 · microphthalmia, isolated 2 · microphthalmia, isolated type 2 · VSX2 isolated microphthalmia

Data availability: 385 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › isolated microphthalmia › isolated microphthalmia 2

Related subtypes (9): microphthalmia, isolated, with coloboma, microphthalmia, isolated, with cataract 1, isolated microphthalmia 1, isolated microphthalmia 3, isolated microphthalmia 5, isolated microphthalmia 4, isolated microphthalmia 6, isolated microphthalmia 7, isolated microphthalmia 8

Subtypes (1): microphthalmia, isolated, with coloboma 3

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

385 retrieved; paginated sample, class counts are floors:

237 likely benign, 61 uncertain significance, 30 pathogenic, 27 conflicting classifications of pathogenicity, 9 benign, 9 likely pathogenic, 7 pathogenic/likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071776	NM_182894.3(VSX2):c.584G>A (p.Trp195Ter)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1374787	NM_182894.3(VSX2):c.84del (p.Arg28fs)	VSX2	Pathogenic	criteria provided, single submitter
1387187	NM_182894.3(VSX2):c.224del (p.Gly75fs)	VSX2	Pathogenic	criteria provided, single submitter
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
1411209	NM_182894.3(VSX2):c.87C>A (p.Cys29Ter)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1412831	NM_182894.3(VSX2):c.50_51insAT (p.Ala18fs)	VSX2	Pathogenic	criteria provided, single submitter
1419627	NM_182894.3(VSX2):c.179dup (p.His60fs)	VSX2	Pathogenic	criteria provided, single submitter
1430257	NM_182894.3(VSX2):c.589C>T (p.Gln197Ter)	VSX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451168	NM_182894.3(VSX2):c.608G>A (p.Trp203Ter)	VSX2	Pathogenic	criteria provided, single submitter
1453132	NM_182894.3(VSX2):c.59del (p.Ser20fs)	VSX2	Pathogenic	criteria provided, single submitter
1457945	NC_000014.8:g.(?74707875)(74712001_?)del	VSX2	Pathogenic	criteria provided, single submitter
14860	NM_182894.3(VSX2):c.599G>A (p.Arg200Gln)	VSX2	Pathogenic	criteria provided, multiple submitters, no conflicts
14861	NM_182894.3(VSX2):c.599G>C (p.Arg200Pro)	VSX2	Pathogenic/Likely 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
14863	NG_013092.1:g.(7926_9509)_(12624_14744)del	VSX2	Pathogenic	no assertion criteria provided
1984660	NM_182894.3(VSX2):c.513del (p.Tyr172fs)	VSX2	Pathogenic	criteria provided, single submitter
2017212	NM_182894.3(VSX2):c.264C>G (p.Tyr88Ter)	VSX2	Pathogenic	criteria provided, single submitter
2022813	NM_182894.3(VSX2):c.15del (p.Glu7fs)	VSX2	Pathogenic	criteria provided, single submitter
2032657	NM_182894.3(VSX2):c.419del (p.Ala139_Leu140insTer)	VSX2	Pathogenic	criteria provided, single submitter
2112771	NM_182894.3(VSX2):c.667G>C (p.Gly223Arg)	VSX2	Pathogenic	criteria provided, single submitter
221962	NM_182894.3(VSX2):c.71dup (p.Ala25fs)	VSX2	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
2427598	NC_000014.8:g.(?74726295)(74727632_?)del	VSX2	Pathogenic	criteria provided, single submitter
2758164	NM_182894.3(VSX2):c.166dup (p.Leu56fs)	VSX2	Pathogenic	criteria provided, single submitter
2764044	NM_182894.3(VSX2):c.634del (p.Arg212fs)	VSX2	Pathogenic	criteria provided, single submitter
2813462	NM_182894.3(VSX2):c.4del (p.Thr2fs)	VSX2	Pathogenic	criteria provided, single submitter
2843544	NM_182894.3(VSX2):c.248_249del (p.Gly83fs)	VSX2	Pathogenic	criteria provided, single submitter
2979108	NM_182894.3(VSX2):c.438del (p.Lys147fs)	VSX2	Pathogenic	criteria provided, single submitter
3000990	NM_182894.3(VSX2):c.249dup (p.Leu84fs)	VSX2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
VSX2	Definitive	Autosomal recessive	microphthalmia, isolated, with coloboma 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VSX2	Orphanet:98938	Colobomatous microphthalmia
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VSX2	HGNC:1975	ENSG00000119614	P58304	Visual system homeobox 2	gencc,clinvar
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	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.
VRK1	Serine/threonine-protein kinase VRK1	Serine/threonine kinase involved in the regulation of key cellular processes including the cell cycle, nuclear condensation, transcription regulation, and DNA damage response.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

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

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VSX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
bone marrow	1
oocyte	1
secondary oocyte	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
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VRK1	3,022
VSX2	1,484

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VRK1	Q99986	26

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VSX2	P58304	61.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.002	VRK1
Nuclear Envelope Breakdown	1	456.8×	0.002	VRK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of protein localization to chromatin	1	2808.7×	0.004	VRK1
Cajal body organization	1	2106.5×	0.004	VRK1
retinal bipolar neuron differentiation	1	1404.3×	0.004	VSX2
Golgi disassembly	1	1404.3×	0.004	VRK1
mitotic nuclear membrane disassembly	1	936.2×	0.005	VRK1
negative regulation of neuroblast proliferation	1	601.9×	0.006	VSX2
regulation of neuron migration	1	312.1×	0.009	VRK1
central nervous system neuron differentiation	1	300.9×	0.009	VSX2
neuroblast proliferation	1	183.2×	0.013	VSX2
cell fate commitment	1	147.8×	0.015	VSX2
protein autophosphorylation	1	72.6×	0.027	VRK1
neuron projection development	1	61.1×	0.030	VRK1
visual perception	1	39.8×	0.042	VSX2
chromatin remodeling	1	36.5×	0.043	VRK1
protein phosphorylation	1	34.0×	0.043	VRK1
DNA damage response	1	26.8×	0.051	VRK1
cell division	1	23.1×	0.055	VRK1
positive regulation of cell population proliferation	1	16.8×	0.072	VSX2
negative regulation of transcription by RNA polymerase II	1	8.9×	0.127	VSX2
signal transduction	1	8.0×	0.133	VRK1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.136	VSX2
regulation of transcription by RNA polymerase II	1	5.8×	0.164	VSX2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VSX2	0	0
VRK1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
VRK1	74	Binding:74

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	VRK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	VSX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VSX2	0	—
VRK1	74	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.