Isolated microphthalmia 5

Summary

Isolated microphthalmia 5 (MONDO:0012605) is a disease caused by MFRP (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MFRP (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 646

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated microphthalmia 5
Mondo ID	MONDO:0012605
MeSH	C567024
OMIM	611040
Orphanet	251279
DOID	DOID:0060837
UMLS	C1970236
MedGen	410021
GARD	0017205
Is cancer (heuristic)	no

Also known as: isolated microphthalmia 5 · isolated microphthalmia caused by mutation in MFRP · isolated microphthalmia type 5 · MCOP5 · MFRP isolated microphthalmia · microphthalmia, isolated 5 · microphthalmia, isolated type 5 · microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome · microphthalmia-retinitis pigmentosa-foveoschisis-optic disk drusen syndrome · Nanophtalmos-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome · Nanophtalmos-retinitis pigmentosa-foveoschisis-optic disk drusen syndrome · posterior microphthalmia with retinitis pigmentosa, foveoschisis and optic disk drusen

Data availability: 646 ClinVar variants · 5 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 5

Related subtypes (9): microphthalmia, isolated, with coloboma, microphthalmia, isolated, with cataract 1, isolated microphthalmia 1, isolated microphthalmia 2, isolated microphthalmia 3, 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

600 retrieved; paginated sample, class counts are floors:

259 uncertain significance, 233 likely benign, 42 pathogenic, 28 conflicting classifications of pathogenicity, 15 benign/likely benign, 9 benign, 9 likely pathogenic, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069330	NM_031433.4(MFRP):c.666del (p.Thr223fs)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts
1070551	NM_031433.4(MFRP):c.313del (p.Leu105fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
1071727	NM_031433.4(MFRP):c.1090_1091del (p.Thr364fs)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts
1074166	NM_031433.4(MFRP):c.1090_1094del (p.Thr364fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
1359963	NM_031433.4(MFRP):c.102C>A (p.Cys34Ter)	C1QTNF5	Pathogenic	criteria provided, single submitter
1442130	NM_031433.4(MFRP):c.1408C>T (p.Gln470Ter)	C1QTNF5	Pathogenic	criteria provided, single submitter
1452557	NM_031433.4(MFRP):c.431_443dup (p.Ser149fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
1458089	NM_031433.4(MFRP):c.287_291del (p.Pro96fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
1706425	NM_031433.4(MFRP):c.662_663insT (p.Thr223fs)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts
183043	NM_031433.4(MFRP):c.951C>A (p.Tyr317Ter)	C1QTNF5	Pathogenic	criteria provided, single submitter
183045	NM_031433.4(MFRP):c.201G>A (p.Trp67Ter)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts
183046	NM_031433.4(MFRP):c.491_492insT (p.Asn167fs)	C1QTNF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1905353	NM_031433.4(MFRP):c.1078G>T (p.Glu360Ter)	C1QTNF5	Pathogenic	criteria provided, single submitter
191026	NM_031433.4(MFRP):c.746G>A (p.Trp249Ter)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts
2024780	NM_031433.4(MFRP):c.1228_1234del (p.Thr410fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
209172	NM_031433.4(MFRP):c.958C>T (p.Gln320Ter)	C1QTNF5	Pathogenic	criteria provided, single submitter
2152209	NM_031433.4(MFRP):c.1150del (p.His384fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
2194741	NM_031433.4(MFRP):c.1333_1334del (p.Asp445fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
2418993	NM_031433.4(MFRP):c.500del (p.Asn167fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
2706696	NM_031433.4(MFRP):c.1506_1507del (p.Ser502fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
2724828	NM_031433.4(MFRP):c.1124+1G>A	C1QTNF5	Pathogenic	criteria provided, single submitter
2780867	NM_031433.4(MFRP):c.909dup (p.Asn304fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
2818349	NM_031433.4(MFRP):c.499_500dup (p.Asn167fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
2907420	NM_031433.4(MFRP):c.577_578del (p.Ser193fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
3698874	NM_031433.4(MFRP):c.754dup (p.Ala252fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
3717132	NM_031433.4(MFRP):c.1296del (p.Cys433fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
3726413	NM_031433.4(MFRP):c.634dup (p.Leu212fs)	C1QTNF5	Pathogenic	criteria provided, single submitter
438224	NM_031433.4(MFRP):c.955C>T (p.Gln319Ter)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts
4474	NM_031433.4(MFRP):c.1150dup (p.His384fs)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts
4475	NM_031433.4(MFRP):c.523C>T (p.Gln175Ter)	C1QTNF5	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
MFRP	Definitive	Autosomal recessive	isolated microphthalmia 5	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MFRP	Orphanet:251279	Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome
MFRP	Orphanet:35612	Nanophthalmos
C1QTNF5	Orphanet:67042	Late-onset retinal degeneration
APOC3	Orphanet:181428	Familial Hyperalphalipoproteinemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MFRP	HGNC:18121	ENSG00000235718	Q9BY79	Membrane frizzled-related protein	gencc,clinvar
C1QTNF5	HGNC:14344	ENSG00000223953	Q9BXJ0	Complement C1q tumor necrosis factor-related protein 5	clinvar
APOC3	HGNC:610	ENSG00000110245	P02656	Apolipoprotein C-III	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MFRP	Membrane frizzled-related protein	May play a role in eye development.
APOC3	Apolipoprotein C-III	Component of triglyceride-rich very low density lipoproteins (VLDL) and high density lipoproteins (HDL) in plasma.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MFRP	Other/Unknown	no		CUB_dom, LDrepeatLR_classA_rpt, Frizzled_dom
C1QTNF5	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
APOC3	Other/Unknown	no		Apo-CIII, Apo_CIII_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)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	1
stromal cell of endometrium	1
sural nerve	1
apex of heart	1
ascending aorta	1
gall bladder	1
jejunal mucosa	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFRP	29	tissue_specific	marker	primordial germ cell in gonad, stromal cell of endometrium, sural nerve
C1QTNF5	128	ubiquitous	yes	apex of heart, gall bladder, ascending aorta
APOC3	156	tissue_specific	marker	jejunal mucosa, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOC3	1,895
MFRP	858
C1QTNF5	369

Intra-cohort edges

A	B	Sources
C1QTNF5	MFRP	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C1QTNF5	Q9BXJ0	2
APOC3	P02656	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MFRP	Q9BY79	73.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Chylomicron assembly	1	1142.0×	0.004	APOC3
Chylomicron remodeling	1	1142.0×	0.004	APOC3
HDL remodeling	1	1142.0×	0.004	APOC3
Plasma lipoprotein assembly	1	713.8×	0.005	APOC3
Plasma lipoprotein remodeling	1	475.8×	0.005	APOC3
Metabolism of fat-soluble vitamins	1	380.7×	0.006	APOC3
Visual phototransduction	1	259.6×	0.006	APOC3
Retinoid metabolism and transport	1	248.3×	0.006	APOC3
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.006	APOC3
Metabolism of vitamins and cofactors	1	116.5×	0.011	APOC3
Sensory Perception	1	95.2×	0.012	APOC3
Transport of small molecules	1	25.1×	0.043	APOC3
Metabolism	1	11.6×	0.086	APOC3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of high-density lipoprotein particle clearance	1	5617.3×	0.004	APOC3
negative regulation of cholesterol import	1	1872.4×	0.004	APOC3
negative regulation of very-low-density lipoprotein particle clearance	1	1404.3×	0.004	APOC3
negative regulation of lipid metabolic process	1	1123.5×	0.004	APOC3
negative regulation of triglyceride catabolic process	1	936.2×	0.004	APOC3
negative regulation of very-low-density lipoprotein particle remodeling	1	936.2×	0.004	APOC3
chylomicron remnant clearance	1	936.2×	0.004	APOC3
negative regulation of receptor-mediated endocytosis	1	624.1×	0.006	APOC3
negative regulation of low-density lipoprotein particle clearance	1	510.7×	0.006	APOC3
regulation of Cdc42 protein signal transduction	1	468.1×	0.006	APOC3
very-low-density lipoprotein particle assembly	1	401.2×	0.006	APOC3
phospholipid efflux	1	374.5×	0.006	APOC3
lipoprotein metabolic process	1	312.1×	0.006	APOC3
reverse cholesterol transport	1	312.1×	0.006	APOC3
negative regulation of fatty acid biosynthetic process	1	295.6×	0.006	APOC3
eye photoreceptor cell development	1	280.9×	0.006	MFRP
negative regulation of lipid catabolic process	1	280.9×	0.006	APOC3
triglyceride catabolic process	1	267.5×	0.006	APOC3
high-density lipoprotein particle remodeling	1	267.5×	0.006	APOC3
embryo development ending in birth or egg hatching	1	244.2×	0.006	MFRP
cholesterol efflux	1	175.5×	0.008	APOC3
triglyceride homeostasis	1	160.5×	0.008	APOC3
triglyceride metabolic process	1	147.8×	0.009	APOC3
inner ear development	1	124.8×	0.010	C1QTNF5
protein secretion	1	87.8×	0.013	C1QTNF5
retina development in camera-type eye	1	85.1×	0.013	MFRP
cholesterol homeostasis	1	52.0×	0.021	APOC3
visual perception	1	26.5×	0.039	MFRP
G protein-coupled receptor signaling pathway	1	12.1×	0.081	APOC3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MFRP	0	0
C1QTNF5	0	0
APOC3	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
APOC3	1	Binding:1

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	MFRP, C1QTNF5, APOC3

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)
MFRP	0	—
C1QTNF5	0	—
APOC3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.