Microcephaly 31, primary, autosomal recessive

Summary

Microcephaly 31, primary, autosomal recessive (MONDO:0980991) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 31, primary, autosomal recessive
Mondo ID	MONDO:0980991
OMIM	621507
DOID	DOID:0051074
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive primary microcephaly › microcephaly 31, primary, autosomal recessive

Related subtypes (28): microcephaly 1, primary, autosomal recessive, microcephaly with simplified gyral pattern, microcephaly 2, primary, autosomal recessive, with or without cortical malformations, microcephaly 4, primary, autosomal recessive, microcephaly 3, primary, autosomal recessive, microcephaly 5, primary, autosomal recessive, microcephaly 7, primary, autosomal recessive, microcephaly 8, primary, autosomal recessive, microcephaly 9, primary, autosomal recessive, microcephalic primordial dwarfism due to ZNF335 deficiency, microcephaly 11, primary, autosomal recessive, microcephaly 13, primary, autosomal recessive, microcephaly 12, primary, autosomal recessive, microcephaly 14, primary, autosomal recessive, microcephaly 15, primary, autosomal recessive, microcephaly 16, primary, autosomal recessive, microcephaly 17, primary, autosomal recessive, microcephaly 28, primary, autosomal recessive, microcephaly 29, primary, autosomal recessive, microcephaly 24, primary, autosomal recessive, microcephaly 25, primary, autosomal recessive, microcephaly 19, primary, autosomal recessive, microcephaly 20, primary, autosomal recessive, microcephaly 21, primary, autosomal recessive, microcephaly 22, primary, autosomal recessive, microcephaly 23, primary, autosomal recessive, microcephaly with or without short stature, microcephaly 30, primary, autosomal recessive

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

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
565432	NM_000075.4(CDK4):c.367C>T (p.Gln123Ter)	CDK4	Uncertain significance	criteria provided, single submitter
835855	NM_000075.4(CDK4):c.218G>A (p.Arg73Gln)	CDK4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDK4	Orphanet:618	Familial melanoma
CDK4	Orphanet:99970	Dedifferentiated liposarcoma
CDK4	Orphanet:99971	Well-differentiated liposarcoma

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
CDK4	HGNC:1773	ENSG00000135446	P11802	Cyclin-dependent kinase 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDK4	Cyclin-dependent kinase 4	Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDK4	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_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)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDK4	138	ubiquitous	marker	embryo, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDK4	8,412

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK4	P11802	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. 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
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4	1	5710.0×	0.002	CDK4
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4	1	5710.0×	0.002	CDK4
Diseases of Cellular Senescence	1	3806.7×	0.002	CDK4
Evasion of Oncogene Induced Senescence Due to p16INK4A Defects	1	3806.7×	0.002	CDK4
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	1	3806.7×	0.002	CDK4
Evasion of Oxidative Stress Induced Senescence Due to p16INK4A Defects	1	3806.7×	0.002	CDK4
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	1	3806.7×	0.002	CDK4
Diseases of cellular response to stress	1	3806.7×	0.002	CDK4
Drug-mediated inhibition of CDK4/CDK6 activity	1	2284.0×	0.002	CDK4
PTK6 Regulates Cell Cycle	1	1903.3×	0.003	CDK4
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1	878.5×	0.005	CDK4
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	634.4×	0.007	CDK4
Signaling by PTK6	1	543.8×	0.007	CDK4
Signaling by Non-Receptor Tyrosine Kinases	1	543.8×	0.007	CDK4
Aberrant regulation of mitotic cell cycle due to RB1 defects	1	407.9×	0.007	CDK4
G1 Phase	1	393.8×	0.007	CDK4
Diseases of mitotic cell cycle	1	393.8×	0.007	CDK4
Oncogene Induced Senescence	1	335.9×	0.008	CDK4
Meiosis	1	285.5×	0.008	CDK4
Cyclin E associated events during G1/S transition	1	285.5×	0.008	CDK4
Cyclin A:Cdk2-associated events at S phase entry	1	265.6×	0.008	CDK4
Ubiquitin-dependent degradation of Cyclin D	1	265.6×	0.008	CDK4
Transcriptional regulation by RUNX2	1	253.8×	0.008	CDK4
G1/S Transition	1	233.1×	0.008	CDK4
Cyclin D associated events in G1	1	233.1×	0.008	CDK4
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	228.4×	0.008	CDK4
SCF(Skp2)-mediated degradation of p27/p21	1	207.6×	0.009	CDK4
Reproduction	1	190.3×	0.009	CDK4
Mitotic G1 phase and G1/S transition	1	184.2×	0.009	CDK4
S Phase	1	181.3×	0.009	CDK4

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
regulation of transcription initiation by RNA polymerase II	1	5617.3×	0.002	CDK4
cellular response to ionomycin	1	2808.7×	0.002	CDK4
regulation of type B pancreatic cell proliferation	1	2106.5×	0.002	CDK4
regulation of G2/M transition of mitotic cell cycle	1	1296.3×	0.002	CDK4
cellular response to phorbol 13-acetate 12-myristate	1	1296.3×	0.002	CDK4
cellular response to interleukin-4	1	648.1×	0.004	CDK4
positive regulation of G2/M transition of mitotic cell cycle	1	601.9×	0.004	CDK4
positive regulation of fibroblast proliferation	1	295.6×	0.007	CDK4
G1/S transition of mitotic cell cycle	1	200.6×	0.009	CDK4
cellular response to lipopolysaccharide	1	98.0×	0.016	CDK4
regulation of gene expression	1	83.4×	0.017	CDK4
regulation of cell cycle	1	74.6×	0.018	CDK4
response to xenobiotic stimulus	1	69.1×	0.018	CDK4
cell division	1	46.2×	0.025	CDK4
positive regulation of cell population proliferation	1	33.6×	0.032	CDK4
signal transduction	1	16.1×	0.062	CDK4

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
CDK4	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK4	56	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	CDK4
ABEMACICLIB	4	CDK4
RIBOCICLIB	4	CDK4
TRILACICLIB	4	CDK4
FEDRATINIB	4	CDK4
DABRAFENIB	4	CDK4
CERITINIB	4	CDK4
ENCORAFENIB	4	CDK4
GILTERITINIB	4	CDK4
NINTEDANIB	4	CDK4
SUNITINIB	4	CDK4
DINACICLIB	3	CDK4
LEROCICLIB	3	CDK4
ALVOCIDIB	3	CDK4
QUERCETIN	3	CDK4
DALPICICLIB	3	CDK4
DOVITINIB	3	CDK4
LESTAURTINIB	3	CDK4
RUBOXISTAURIN	3	CDK4
INDIRUBIN	2	CDK4
SELICICLIB	2	CDK4
REBASTINIB	2	CDK4
NARAZACICLIB	2	CDK4
RIVICICLIB	2	CDK4
RG-547	2	CDK4
VORUCICLIB	2	CDK4
ULECACICLIB	2	CDK4
CROZBACICLIB	2	CDK4
RONICICLIB	2	CDK4
EBVACICLIB	2	CDK4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDK4	1,142	Binding:1086, Functional:53, ADMET:2, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDK4	2.7.11.22	cyclin-dependent kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CDK4	1,142

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

30 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	CDK4
ABEMACICLIB	4	CDK4
RIBOCICLIB	4	CDK4
TRILACICLIB	4	CDK4
FEDRATINIB	4	CDK4
DABRAFENIB	4	CDK4
CERITINIB	4	CDK4
ENCORAFENIB	4	CDK4
GILTERITINIB	4	CDK4
NINTEDANIB	4	CDK4
SUNITINIB	4	CDK4
DINACICLIB	3	CDK4
LEROCICLIB	3	CDK4
ALVOCIDIB	3	CDK4
QUERCETIN	3	CDK4
DALPICICLIB	3	CDK4
DOVITINIB	3	CDK4
LESTAURTINIB	3	CDK4
RUBOXISTAURIN	3	CDK4
INDIRUBIN	2	CDK4
SELICICLIB	2	CDK4
REBASTINIB	2	CDK4
NARAZACICLIB	2	CDK4
RIVICICLIB	2	CDK4
RG-547	2	CDK4
VORUCICLIB	2	CDK4
ULECACICLIB	2	CDK4
CROZBACICLIB	2	CDK4
RONICICLIB	2	CDK4
EBVACICLIB	2	CDK4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDK4
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.