Microphthalmia, isolated, with coloboma 3

Summary

Microphthalmia, isolated, with coloboma 3 (MONDO:0012408) is a disease caused by VSX2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: VSX2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 93

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microphthalmia, isolated, with coloboma 3
Mondo ID	MONDO:0012408
MeSH	C566447
OMIM	610092
UMLS	C1864721
MedGen	400598
GARD	0015471
Is cancer (heuristic)	no

Also known as: MCOPCB3 · microphthalmia with coloboma 3 · microphthalmia, isolated, with coloboma 3 · microphthalmia, isolated, with coloboma caused by mutation in VSX2 · microphthalmia, isolated, with coloboma type 3 · VSX2 microphthalmia, isolated, with coloboma

Data availability: 93 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › isolated microphthalmia › microphthalmia, isolated, with coloboma › microphthalmia, isolated, with coloboma 3

Related subtypes (11): microphthalmia, isolated, with coloboma 4, microphthalmia with coloboma 2, microphthalmia, isolated, with coloboma 5, microphthalmia, isolated, with coloboma 6, microphthalmia, isolated, with coloboma 7, microphthalmia, isolated, with coloboma 9, microphthalmia, isolated, with coloboma 10, microphthalmia with coloboma 1, microphthalmia, isolated, with coloboma 8, microphthalmia/coloboma 11, microphthalmia/coloboma 13

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

93 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 23 conflicting classifications of pathogenicity, 6 likely pathogenic, 5 benign, 5 likely benign, 4 pathogenic/likely pathogenic, 4 benign/likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1387606	NM_182894.3(VSX2):c.371-1G>A	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
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
4081830	NM_182894.3(VSX2):c.316C>T (p.Gln106Ter)	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
3576730	NM_182894.3(VSX2):c.2T>C (p.Met1Thr)	VSX2	Likely pathogenic	criteria provided, single submitter
3576731	NM_182894.3(VSX2):c.106G>T (p.Glu36Ter)	VSX2	Likely pathogenic	criteria provided, single submitter
3576732	NM_182894.3(VSX2):c.307_308insGG (p.Val103fs)	VSX2	Likely pathogenic	criteria provided, single submitter
3576733	NM_182894.3(VSX2):c.456-6C>G	VSX2	Likely pathogenic	criteria provided, single submitter
3576734	NM_182894.3(VSX2):c.695del (p.Leu232fs)	VSX2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780790	NM_182894.3(VSX2):c.331dup (p.Ala111fs)	VSX2	Likely pathogenic	criteria provided, single submitter
167839	NM_182894.3(VSX2):c.299C>A (p.Pro100Gln)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285031	NM_182894.3(VSX2):c.244G>A (p.Gly82Arg)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314195	NM_182894.3(VSX2):c.579G>A (p.Gln193=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314196	NM_182894.3(VSX2):c.750G>A (p.Pro250=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314197	NM_182894.3(VSX2):c.777G>A (p.Ser259=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314198	NM_182894.3(VSX2):c.777G>T (p.Ser259=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314199	NM_182894.3(VSX2):c.810C>G (p.Pro270=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314203	NM_182894.3(VSX2):c.939T>A (p.Ala313=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314208	NM_182894.3(VSX2):c.*54G>A	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314219	NM_182894.3(VSX2):c.*1161C>A	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314222	NM_182894.3(VSX2):c.*1311G>A	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314224	NM_182894.3(VSX2):c.*1377C>T	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
468358	NM_182894.3(VSX2):c.162C>A (p.Asp54Glu)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
468359	NM_182894.3(VSX2):c.504C>T (p.Asn168=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
705711	NM_182894.3(VSX2):c.699C>T (p.Pro233=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706510	NM_182894.3(VSX2):c.249G>A (p.Gly83=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706589	NM_182894.3(VSX2):c.171C>G (p.Ala57=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
738345	NM_182894.3(VSX2):c.564G>A (p.Pro188=)	VSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · 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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VSX2	HGNC:1975	ENSG00000119614	P58304	Visual system homeobox 2	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VSX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	0
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

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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VSX2	1,484

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VSX2	P58304	61.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retinal bipolar neuron differentiation	1	2808.7×	0.004	VSX2
negative regulation of neuroblast proliferation	1	1203.7×	0.004	VSX2
central nervous system neuron differentiation	1	601.9×	0.006	VSX2
neuroblast proliferation	1	366.4×	0.007	VSX2
cell fate commitment	1	295.6×	0.007	VSX2
visual perception	1	79.5×	0.021	VSX2
positive regulation of cell population proliferation	1	33.6×	0.042	VSX2
negative regulation of transcription by RNA polymerase II	1	17.7×	0.071	VSX2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.075	VSX2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	VSX2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	VSX2

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.