Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

Summary

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (MONDO:0014408) is a disease caused by CCND2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CCND2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3
Mondo ID	MONDO:0014408
OMIM	615938
UMLS	C4014742
MedGen	863179
GARD	0018079
Is cancer (heuristic)	no

Also known as: CCND2 megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome · megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 · megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome type 3 · megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome caused by mutation in CCND2 · MPPH3

Data availability: 20 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › hydrocephalus › megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome › megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

Related subtypes (2): megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

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

20 retrieved; paginated sample, class counts are floors:

4 pathogenic, 4 pathogenic/likely pathogenic, 4 uncertain significance, 2 benign, 2 benign/likely benign, 2 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
143981	NM_001759.4(CCND2):c.838A>G (p.Thr280Ala)	CCND2	Pathogenic	criteria provided, multiple submitters, no conflicts
143982	NM_001759.4(CCND2):c.808A>T (p.Lys270Ter)	CCND2	Pathogenic	criteria provided, single submitter
143983	NM_001759.4(CCND2):c.839C>A (p.Thr280Asn)	CCND2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143984	NM_001759.4(CCND2):c.841C>T (p.Pro281Ser)	CCND2	Pathogenic	criteria provided, multiple submitters, no conflicts
143986	NM_001759.4(CCND2):c.842C>T (p.Pro281Leu)	CCND2	Pathogenic	criteria provided, single submitter
3254550	NM_001759.4(CCND2):c.838A>C (p.Thr280Pro)	CCND2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666559	NM_001759.4(CCND2):c.839C>T (p.Thr280Ile)	CCND2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
987230	NM_001759.4(CCND2):c.829C>T (p.Gln277Ter)	CCND2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2504114	NM_001759.4(CCND2):c.812C>A (p.Ser271Ter)	CCND2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775676	NM_001759.4(CCND2):c.802G>T (p.Gly268Ter)	CCND2	Likely pathogenic	criteria provided, single submitter
143985	NM_001759.4(CCND2):c.842C>G (p.Pro281Arg)	CCND2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805679	NM_001759.4(CCND2):c.559C>G (p.Leu187Val)	CCND2	Uncertain significance	criteria provided, single submitter
2439813	NM_001759.4(CCND2):c.494G>A (p.Arg165His)	CCND2	Uncertain significance	criteria provided, single submitter
3066255	NM_001759.4(CCND2):c.196-1G>A	CCND2	Uncertain significance	criteria provided, single submitter
3237411	NM_001759.4(CCND2):c.774G>C (p.Leu258=)	CCND2	Uncertain significance	criteria provided, single submitter
1192627	NM_001759.4(CCND2):c.-49T>C	CCND2	Benign	criteria provided, multiple submitters, no conflicts
1280659	NM_001759.4(CCND2):c.802G>A (p.Gly268Arg)	CCND2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
380772	NM_001759.4(CCND2):c.570C>G (p.Thr190=)	CCND2	Benign	criteria provided, multiple submitters, no conflicts
511836	NM_001759.4(CCND2):c.756G>A (p.Ala252=)	CCND2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
273674	NM_001759.4(CCND2):c.851T>G (p.Val284Gly)	CCND2	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
CCND2	Definitive	Autosomal dominant	megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CCND2	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

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
CCND2	HGNC:1583	ENSG00000118971	P30279	G1/S-specific cyclin-D2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CCND2	G1/S-specific cyclin-D2	Regulatory component of the cyclin D2-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CCND2	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom

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)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
cauda epididymis	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCND2	293	ubiquitous	marker	adrenal tissue, seminal vesicle, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCND2	3,569

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCND2	P30279	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 1 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
Drug-mediated inhibition of CDK4/CDK6 activity	1	2284.0×	0.006	CCND2
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1	878.5×	0.006	CCND2
Regulation of RUNX1 Expression and Activity	1	671.8×	0.006	CCND2
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	634.4×	0.006	CCND2
Aberrant regulation of mitotic cell cycle due to RB1 defects	1	407.9×	0.006	CCND2
G1 Phase	1	393.8×	0.006	CCND2
Diseases of mitotic cell cycle	1	393.8×	0.006	CCND2
Cyclin D associated events in G1	1	233.1×	0.009	CCND2
Mitotic G1 phase and G1/S transition	1	184.2×	0.010	CCND2
Transcriptional regulation by RUNX1	1	146.4×	0.011	CCND2
Cell Cycle, Mitotic	1	48.2×	0.030	CCND2
Cell Cycle	1	36.0×	0.037	CCND2
RNA Polymerase II Transcription	1	22.5×	0.055	CCND2
Gene expression (Transcription)	1	17.8×	0.064	CCND2
Generic Transcription Pathway	1	15.1×	0.071	CCND2
Disease	1	13.1×	0.076	CCND2

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
cellular response to X-ray	1	1685.2×	0.005	CCND2
long-term memory	1	421.3×	0.007	CCND2
positive regulation of G1/S transition of mitotic cell cycle	1	401.2×	0.007	CCND2
adult locomotory behavior	1	300.9×	0.007	CCND2
G1/S transition of mitotic cell cycle	1	200.6×	0.008	CCND2
cell division	1	46.2×	0.029	CCND2
negative regulation of apoptotic process	1	34.8×	0.030	CCND2
positive regulation of cell population proliferation	1	33.6×	0.030	CCND2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CCND2	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCND2	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	CCND2
ALVOCIDIB	3	CCND2
BMS-387032	1	CCND2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CCND2	28	Binding:28

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

3 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.

Compound	Max phase	Cohort target (bioactivity)
PALBOCICLIB	4	CCND2
ALVOCIDIB	3	CCND2
BMS-387032	1	CCND2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CCND2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.