Isolated microphthalmia 3

Summary

Isolated microphthalmia 3 (MONDO:0012604) is a disease caused by RAX (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: RAX (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 116

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated microphthalmia 3
Mondo ID	MONDO:0012604
MeSH	C567025
OMIM	611038
DOID	DOID:0060842
UMLS	C5774181
MedGen	1823955
GARD	0024876
Is cancer (heuristic)	no

Also known as: isolated microphthalmia 3 · isolated microphthalmia caused by mutation in RAX · isolated microphthalmia caused by mutation in rax · isolated microphthalmia type 3 · MCOP3 · microphthalmia, isolated 3 · microphthalmia, isolated type 3 · RAX isolated microphthalmia · rax isolated microphthalmia

Data availability: 116 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 › isolated microphthalmia 3

Related subtypes (9): microphthalmia, isolated, with coloboma, microphthalmia, isolated, with cataract 1, isolated microphthalmia 1, isolated microphthalmia 2, isolated microphthalmia 5, isolated microphthalmia 4, isolated microphthalmia 6, isolated microphthalmia 7, isolated microphthalmia 8

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

116 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 26 likely benign, 7 pathogenic, 7 benign, 7 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
7637	NM_013435.3(RAX):c.664del (p.Ser222fs)	LOC130062601	Pathogenic	no assertion criteria provided
2425868	NC_000018.9:g.(?55217944)(58040587_?)del	MIR122	Pathogenic	criteria provided, single submitter
1723189	NM_013435.3(RAX):c.560G>A (p.Arg187Gln)	RAX	Pathogenic	no assertion criteria provided
1723190	NM_013435.3(RAX):c.266del (p.Pro89fs)	RAX	Pathogenic	no assertion criteria provided
7635	NM_013435.3(RAX):c.439C>T (p.Gln147Ter)	RAX	Pathogenic	no assertion criteria provided
7636	NM_013435.3(RAX):c.575G>A (p.Arg192Gln)	RAX	Pathogenic	no assertion criteria provided
7638	NM_013435.3(RAX):c.909C>G (p.Tyr303Ter)	RAX	Pathogenic	no assertion criteria provided
1723188	NM_013435.3(RAX):c.543+3A>G	RAX	Likely pathogenic	criteria provided, single submitter
3583379	NM_013435.3(RAX):c.50_53dup (p.Gly19fs)	RAX	Likely pathogenic	criteria provided, single submitter
772773	NM_013435.3(RAX):c.783G>C (p.Pro261=)	LOC130062601	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327533	NM_013435.3(RAX):c.544-11C>G	RAX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
496932	NM_013435.3(RAX):c.197G>C (p.Arg66Thr)	RAX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
766849	NM_013435.3(RAX):c.290-4C>A	RAX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
767328	NM_013435.3(RAX):c.24A>G (p.Pro8=)	RAX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
889866	NM_013435.3(RAX):c.-94G>A	RAX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892542	NM_013435.3(RAX):c.612G>A (p.Leu204=)	RAX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
645205	NM_013435.3(RAX):c.697G>T (p.Gly233Trp)	LOC130062601	Uncertain significance	criteria provided, single submitter
1363557	NM_013435.3(RAX):c.286G>C (p.Glu96Gln)	RAX	Uncertain significance	criteria provided, multiple submitters, no conflicts
1442550	NM_013435.3(RAX):c.202G>A (p.Gly68Ser)	RAX	Uncertain significance	criteria provided, single submitter
1801041	NM_013435.3(RAX):c.497G>C (p.Arg166Pro)	RAX	Uncertain significance	criteria provided, multiple submitters, no conflicts
2055375	NM_013435.3(RAX):c.867G>T (p.Leu289Phe)	RAX	Uncertain significance	criteria provided, multiple submitters, no conflicts
2127199	NM_013435.3(RAX):c.538G>C (p.Val180Leu)	RAX	Uncertain significance	criteria provided, single submitter
2431587	NM_013435.3(RAX):c.544G>A (p.Val182Met)	RAX	Uncertain significance	criteria provided, single submitter
327502	NM_013435.3(RAX):c.*1817A>G	RAX	Uncertain significance	criteria provided, single submitter
327503	NM_013435.3(RAX):c.*1756C>A	RAX	Uncertain significance	criteria provided, single submitter
327505	NM_013435.3(RAX):c.*1737C>A	RAX	Uncertain significance	criteria provided, single submitter
327506	NM_013435.3(RAX):c.*1547G>T	RAX	Uncertain significance	criteria provided, single submitter
327507	NM_013435.3(RAX):c.*1525G>A	RAX	Uncertain significance	criteria provided, single submitter
327509	NM_013435.3(RAX):c.*1437G>T	RAX	Uncertain significance	criteria provided, single submitter
327510	NM_013435.3(RAX):c.*1389C>G	RAX	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · 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
PRKRA	Definitive	Autosomal recessive	isolated microphthalmia 3	10
RAX	Definitive	Autosomal recessive	isolated microphthalmia 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAX	Orphanet:35612	Nanophthalmos
RAX	Orphanet:98938	Colobomatous microphthalmia
PRKRA	Orphanet:210571	Dystonia 16

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAX	HGNC:18662	ENSG00000134438	Q9Y2V3	Retinal homeobox protein Rx	gencc,clinvar
PRKRA	HGNC:9438	ENSG00000180228	O75569	Interferon-inducible double-stranded RNA-dependent protein kinase activator A	gencc,clinvar
MIR122	HGNC:31501	ENSG00000284440		microRNA 122	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAX	Retinal homeobox protein Rx	Plays a critical role in eye formation by regulating the initial specification of retinal cells and/or their subsequent proliferation.
PRKRA	Interferon-inducible double-stranded RNA-dependent protein kinase activator A	Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
PRKRA	Other/Unknown	no		dsRBD_dom, PRKRA_DSRM_1, PRKRA_DSRM_2
MIR122	Other/Unknown	no

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)	1
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	2
nasal cavity epithelium	1
parotid gland	1
skeletal muscle tissue of biceps brachii	1
sperm	1
liver	1
midbrain	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAX	29	tissue_specific	marker	parotid gland, nasal cavity epithelium, biceps brachii
PRKRA	294	ubiquitous	marker	sperm, skeletal muscle tissue of biceps brachii, biceps brachii
MIR122	2		yes	liver, midbrain

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKRA	2,410
RAX	425
MIR122	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKRA	O75569	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAX	Q9Y2V3	65.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Small interfering RNA (siRNA) biogenesis	1	1142.0×	0.003	PRKRA
MicroRNA (miRNA) biogenesis	1	456.8×	0.003	PRKRA
PKR-mediated signaling	1	141.0×	0.007	PRKRA

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
regulation of regulatory ncRNA processing	1	2808.7×	0.006	PRKRA
siRNA processing	1	936.2×	0.006	PRKRA
outer ear morphogenesis	1	766.0×	0.006	PRKRA
RISC complex assembly	1	766.0×	0.006	PRKRA
pre-miRNA processing	1	561.7×	0.006	PRKRA
hypothalamus development	1	526.6×	0.006	RAX
miRNA processing	1	526.6×	0.006	PRKRA
middle ear morphogenesis	1	351.1×	0.008	PRKRA
skeletal system morphogenesis	1	247.8×	0.009	PRKRA
positive regulation of intrinsic apoptotic signaling pathway	1	240.7×	0.009	PRKRA
pattern specification process	1	234.1×	0.009	RAX
limb development	1	205.5×	0.009	RAX
camera-type eye development	1	179.3×	0.009	RAX
antiviral innate immune response	1	113.9×	0.014	PRKRA
cellular response to oxidative stress	1	77.3×	0.019	PRKRA
response to virus	1	72.0×	0.019	PRKRA
visual perception	1	39.8×	0.032	RAX
protein stabilization	1	33.4×	0.036	PRKRA
immune response	1	23.5×	0.049	PRKRA
negative regulation of cell population proliferation	1	21.1×	0.052	PRKRA
positive regulation of transcription by RNA polymerase II	1	7.4×	0.136	RAX
regulation of transcription by RNA polymerase II	1	5.8×	0.164	RAX

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
RAX	0	0
PRKRA	0	0
MIR122	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	RAX, PRKRA, MIR122

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RAX	0	—
PRKRA	0	—
MIR122	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.