Microphthalmia, isolated, with coloboma 6

Summary

Microphthalmia, isolated, with coloboma 6 (MONDO:0013376) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 397

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microphthalmia, isolated, with coloboma 6
Mondo ID	MONDO:0013376
OMIM	613703
UMLS	C3150968
MedGen	462318
GARD	0015692
Is cancer (heuristic)	no

Also known as: MCOPCB6 · microphthalmia with coloboma 6 · microphthalmia with coloboma 6, digenic · microphthalmia, isolated, with coloboma 6 · microphthalmia, isolated, with coloboma type 6

Data availability: 397 ClinVar variants · 1 GenCC gene-disease record.

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 6

Related subtypes (11): microphthalmia, isolated, with coloboma 4, microphthalmia with coloboma 2, microphthalmia, isolated, with coloboma 3, microphthalmia, isolated, with coloboma 5, 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

397 retrieved; paginated sample, class counts are floors:

201 uncertain significance, 149 likely benign, 24 conflicting classifications of pathogenicity, 15 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30591	NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)	GDF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30593	NM_020634.3(GDF3):c.584G>A (p.Arg195Gln)	GDF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002016	NM_001001557.4(GDF6):c.536C>A (p.Pro179Gln)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023649	NM_001001557.4(GDF6):c.902A>G (p.Glu301Gly)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1094356	NM_001001557.4(GDF6):c.407-3C>T	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400072	NM_001001557.4(GDF6):c.923_928dup (p.306GA[3])	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1404300	NM_001001557.4(GDF6):c.959C>G (p.Pro320Arg)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1938713	NM_001001557.4(GDF6):c.219C>A (p.Asp73Glu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1959955	NM_001001557.4(GDF6):c.454G>A (p.Val152Met)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286405	NM_001001557.4(GDF6):c.725C>G (p.Ala242Gly)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2927707	NM_001001557.4(GDF6):c.625C>T (p.Pro209Ser)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364042	NM_001001557.4(GDF6):c.1304C>T (p.Ala435Val)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364044	NM_001001557.4(GDF6):c.957C>A (p.Ala319=)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364047	NM_001001557.4(GDF6):c.770C>T (p.Pro257Leu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60534	NM_001001557.4(GDF6):c.169G>C (p.Asp57His)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
707560	NM_001001557.4(GDF6):c.24C>G (p.Leu8=)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
707574	NM_001001557.4(GDF6):c.112G>C (p.Gly38Arg)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
836995	NM_001001557.4(GDF6):c.815C>T (p.Pro272Leu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8371	NM_001001557.4(GDF6):c.746C>A (p.Ala249Glu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8372	NM_001001557.4(GDF6):c.866T>C (p.Leu289Pro)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8373	NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
863448	NM_001001557.4(GDF6):c.322G>A (p.Ala108Thr)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914077	NM_001001557.4(GDF6):c.250G>A (p.Glu84Lys)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914078	NM_001001557.4(GDF6):c.18C>T (p.Val6=)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30594	NM_020634.3(GDF3):c.820C>T (p.Arg274Trp)	GDF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3893109	NM_020634.3(GDF3):c.236G>T (p.Arg79Leu)	GDF3	Uncertain significance	criteria provided, single submitter
3893110	NM_020634.3(GDF3):c.890G>T (p.Cys297Phe)	GDF3	Uncertain significance	criteria provided, single submitter
68474	NM_020634.3(GDF3):c.974C>T (p.Pro325Leu)	GDF3	Uncertain significance	no assertion criteria provided
1001816	NM_001001557.4(GDF6):c.1310A>G (p.Asn437Ser)	GDF6	Uncertain significance	criteria provided, single submitter
1002101	NM_001001557.4(GDF6):c.896C>T (p.Ser299Leu)	GDF6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 6 · 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
GDF3	Supportive	Autosomal dominant	isolated Klippel-Feil syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDF3	Orphanet:2345	Isolated Klippel-Feil syndrome
GDF3	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

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
GDF3	HGNC:4218	ENSG00000184344	Q9NR23	Growth/differentiation factor 3	gencc,clinvar
PLEKHF2	HGNC:20757	ENSG00000175895	Q9H8W4	Pleckstrin homology domain-containing family F member 2	clinvar
GDF6	HGNC:4221	ENSG00000156466	Q6KF10	Growth/differentiation factor 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDF3	Growth/differentiation factor 3	Growth factor involved in early embryonic development and adipose-tissue homeostasis.
PLEKHF2	Pleckstrin homology domain-containing family F member 2	May play a role in early endosome fusion upstream of RAB5, hence regulating receptor trafficking and fluid-phase transport.
GDF6	Growth/differentiation factor 6	Growth factor that controls proliferation and cellular differentiation in the retina and bone formation.

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)
GDF3	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_CS
PLEKHF2	Transcription factor	no		Znf_FYVE, PH_domain, Znf_FYVE_PHD
GDF6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like

Expression context

Cohort genes with no expression data: 0.

3 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	2
male germ line stem cell (sensu Vertebrata) in testis	1
type B pancreatic cell	1
oocyte	1
secondary oocyte	1
upper leg skin	1
placenta	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDF3	82	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, type B pancreatic cell
PLEKHF2	268	ubiquitous	marker	secondary oocyte, oocyte, upper leg skin
GDF6	104	broad	marker	placenta, primordial germ cell in gonad, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEKHF2	1,324
GDF6	1,127
GDF3	1,113

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLEKHF2	Q9H8W4	87.36
GDF3	Q9NR23	82.72
GDF6	Q6KF10	70.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
BMP signaling pathway	2	133.8×	0.002	GDF3, GDF6
cell migration involved in metanephros development	1	5617.3×	0.003	GDF6
negative regulation of epidermal cell differentiation	1	2808.7×	0.003	GDF3
retinal cell apoptotic process	1	2808.7×	0.003	GDF6
regulation of cell fate commitment	1	1872.4×	0.003	GDF3
formation of anatomical boundary	1	1404.3×	0.004	GDF3
notochord development	1	561.7×	0.007	GDF3
somite rostral/caudal axis specification	1	510.7×	0.007	GDF3
primitive streak formation	1	468.1×	0.007	GDF3
response to dietary excess	1	374.5×	0.008	GDF3
epithelial cell migration	1	312.1×	0.009	GDF6
activin receptor signaling pathway	1	295.6×	0.009	GDF6
positive regulation of chondrocyte differentiation	1	267.5×	0.009	GDF6
endoderm development	1	208.1×	0.009	GDF3
negative regulation of myoblast differentiation	1	208.1×	0.009	GDF3
positive regulation of p38MAPK cascade	1	208.1×	0.009	GDF6
mesoderm development	1	175.5×	0.010	GDF3
metanephros development	1	170.2×	0.010	GDF6
positive regulation of SMAD protein signal transduction	1	127.7×	0.012	GDF6
endosome organization	1	124.8×	0.012	PLEKHF2
eye development	1	117.0×	0.013	GDF3
endosome to lysosome transport	1	112.3×	0.013	PLEKHF2
positive regulation of fat cell differentiation	1	100.3×	0.013	GDF3
negative regulation of BMP signaling pathway	1	96.8×	0.013	GDF3
positive regulation of neuron differentiation	1	66.1×	0.019	GDF6
fat cell differentiation	1	60.4×	0.020	GDF6
skeletal system development	1	41.9×	0.027	GDF3
in utero embryonic development	1	24.0×	0.045	GDF3
protein transport	1	14.6×	0.071	PLEKHF2
apoptotic process	1	9.6×	0.104	GDF6

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
GDF3	0	0
PLEKHF2	0	0
GDF6	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	GDF3, PLEKHF2, GDF6

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)
GDF3	0	—
PLEKHF2	0	—
GDF6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.