Microcephaly 3, primary, autosomal recessive

Summary

Microcephaly 3, primary, autosomal recessive (MONDO:0011488) is a disease caused by CDK5RAP2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CDK5RAP2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 210

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 3, primary, autosomal recessive
Mondo ID	MONDO:0011488
MeSH	C565746
OMIM	604804
DOID	DOID:0070286
UMLS	C1858108
MedGen	347619
GARD	0015373
Is cancer (heuristic)	no

Also known as: autosomal recessive primary microcephaly caused by mutation in CDK5RAP2 · CDK5RAP2 autosomal recessive primary microcephaly · MCPH3 · microcephaly 3, primary, autosomal recessive

Data availability: 210 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 › autosomal genetic disease › autosomal recessive disease › autosomal recessive primary microcephaly › microcephaly 3, 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 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, microcephaly 31, 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

210 retrieved; paginated sample, class counts are floors:

96 uncertain significance, 44 conflicting classifications of pathogenicity, 27 pathogenic, 14 likely pathogenic, 11 benign, 9 not provided, 6 benign/likely benign, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029683	NM_018249.6(CDK5RAP2):c.1279C>T (p.Arg427Ter)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1177460	NM_018249.6(CDK5RAP2):c.564_565dup (p.Lys189fs)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
127196	NM_018249.6(CDK5RAP2):c.524_528del (p.Gln175fs)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1322052	NM_018249.6(CDK5RAP2):c.3545_3546del (p.His1182fs)	CDK5RAP2	Pathogenic	criteria provided, single submitter
1322053	NM_018249.6(CDK5RAP2):c.355G>T (p.Glu119Ter)	CDK5RAP2	Pathogenic	criteria provided, single submitter
158146	NM_018249.6(CDK5RAP2):c.4005-1G>A	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
158152	NM_018249.6(CDK5RAP2):c.4441C>T (p.Arg1481Ter)	CDK5RAP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158157	NM_018249.6(CDK5RAP2):c.5227C>T (p.Gln1743Ter)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1802606	NM_018249.6(CDK5RAP2):c.558_559del (p.Glu186fs)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
209966	NM_018249.6(CDK5RAP2):c.3097del (p.Val1033fs)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
209967	NM_018249.6(CDK5RAP2):c.4604+1G>C	CDK5RAP2	Pathogenic	criteria provided, single submitter
210631	NM_018249.6(CDK5RAP2):c.1018del (p.Glu340fs)	CDK5RAP2	Pathogenic	criteria provided, single submitter
210637	NM_018249.6(CDK5RAP2):c.4207C>T (p.Arg1403Ter)	CDK5RAP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2488	NM_018249.6(CDK5RAP2):c.246T>A (p.Tyr82Ter)	CDK5RAP2	Pathogenic	no assertion criteria provided
2489	NM_018249.6(CDK5RAP2):c.4005-15A>G	CDK5RAP2	Pathogenic	no assertion criteria provided
3063572	NM_018249.6(CDK5RAP2):c.217_220del (p.Glu73fs)	CDK5RAP2	Pathogenic	no assertion criteria provided
3064144	NM_018249.6(CDK5RAP2):c.3851T>A (p.Leu1284Ter)	CDK5RAP2	Pathogenic	criteria provided, single submitter
3233369	NM_018249.6(CDK5RAP2):c.1865C>G (p.Ser622Ter)	CDK5RAP2	Pathogenic	criteria provided, single submitter
3336691	NM_018249.6(CDK5RAP2):c.4421del (p.Gln1474fs)	CDK5RAP2	Pathogenic	no assertion criteria provided
3336693	NM_018249.6(CDK5RAP2):c.3460C>T (p.Gln1154Ter)	CDK5RAP2	Pathogenic	no assertion criteria provided
3336694	NM_018249.6(CDK5RAP2):c.625dup (p.Asp209fs)	CDK5RAP2	Pathogenic	no assertion criteria provided
430628	NM_018249.6(CDK5RAP2):c.5127_5128dup (p.Ser1710fs)	CDK5RAP2	Pathogenic	no assertion criteria provided
446421	NM_018249.6(CDK5RAP2):c.4670_4671del (p.Leu1557fs)	CDK5RAP2	Pathogenic	criteria provided, single submitter
4681193	NM_018249.6(CDK5RAP2):c.199del (p.Ile67fs)	CDK5RAP2	Pathogenic	criteria provided, single submitter
4813581	NM_018249.6(CDK5RAP2):c.3792del (p.His1264fs)	CDK5RAP2	Pathogenic	criteria provided, single submitter
694012	NM_018249.6(CDK5RAP2):c.1376del (p.Asn459fs)	CDK5RAP2	Pathogenic	no assertion criteria provided
91405	NM_018249.6(CDK5RAP2):c.700G>T (p.Glu234Ter)	CDK5RAP2	Pathogenic	no assertion criteria provided
91406	NM_018249.6(CDK5RAP2):c.4546G>T (p.Glu1516Ter)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
91407	NM_018249.6(CDK5RAP2):c.4672C>T (p.Arg1558Ter)	CDK5RAP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1048514	NM_018249.6(CDK5RAP2):c.4963+1G>A	CDK5RAP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts

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
CDK5RAP2	Strong	Autosomal recessive	microcephaly 3, primary, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDK5RAP2	Orphanet:2512	Autosomal recessive primary microcephaly

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
CDK5RAP2	HGNC:18672	ENSG00000136861	Q96SN8	CDK5 regulatory subunit-associated protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDK5RAP2	CDK5 regulatory subunit-associated protein 2	Potential regulator of CDK5 activity via its interaction with CDK5R1.

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)
CDK5RAP2	Other/Unknown	no		Cnn_1N, CDK5RAP2, CDK5RAP2_MYOME_CC

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
right coronary artery	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDK5RAP2	272	ubiquitous	marker	sural nerve, ventricular zone, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDK5RAP2	1,287

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK5RAP2	Q96SN8	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Loss of Nlp from mitotic centrosomes	1	158.6×	0.009	CDK5RAP2
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.009	CDK5RAP2
AURKA Activation by TPX2	1	152.3×	0.009	CDK5RAP2
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.009	CDK5RAP2
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.009	CDK5RAP2
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.009	CDK5RAP2
Anchoring of the basal body to the plasma membrane	1	113.1×	0.009	CDK5RAP2

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
negative regulation of centriole replication	1	2407.4×	0.004	CDK5RAP2
regulation of mitotic cell cycle spindle assembly checkpoint	1	2106.5×	0.004	CDK5RAP2
microtubule organizing center organization	1	1404.3×	0.004	CDK5RAP2
centriole replication	1	732.7×	0.004	CDK5RAP2
regulation of neuron differentiation	1	732.7×	0.004	CDK5RAP2
positive regulation of microtubule polymerization	1	674.1×	0.004	CDK5RAP2
microtubule bundle formation	1	510.7×	0.004	CDK5RAP2
establishment of mitotic spindle orientation	1	481.5×	0.004	CDK5RAP2
centrosome cycle	1	337.0×	0.005	CDK5RAP2
negative regulation of neuron differentiation	1	271.8×	0.006	CDK5RAP2
neurogenesis	1	208.1×	0.007	CDK5RAP2
chromosome segregation	1	173.7×	0.007	CDK5RAP2
microtubule cytoskeleton organization	1	121.2×	0.010	CDK5RAP2
brain development	1	79.5×	0.013	CDK5RAP2
positive regulation of DNA-templated transcription	1	27.9×	0.036	CDK5RAP2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
CDK5RAP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	CDK5RAP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDK5RAP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.