Microcephaly 1, primary, autosomal recessive

Summary

Microcephaly 1, primary, autosomal recessive (MONDO:0009617) is a disease caused by MCPH1 (GenCC Definitive), with 7 cohort genes.

At a glance

• Causal gene: MCPH1 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 245

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 1, primary, autosomal recessive
Mondo ID	MONDO:0009617
MeSH	C565384
OMIM	251200
Orphanet	52183
DOID	DOID:0070285
UMLS	C1855081
MedGen	344415
GARD	0015198
Is cancer (heuristic)	no

Also known as: autosomal recessive primary microcephaly caused by mutation in MCPH1 · MCPH1 · MCPH1 autosomal recessive primary microcephaly · microcephaly 1, primary, autosomal recessive · premature chromosome condensation with microcephaly and mental retardation

Data availability: 245 ClinVar variants · 2 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 1, primary, autosomal recessive

Related subtypes (28): 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, 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

245 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 60 conflicting classifications of pathogenicity, 45 likely pathogenic, 22 pathogenic, 21 benign, 9 pathogenic/likely pathogenic, 9 benign/likely benign, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
21569	NM_018136.5(ASPM):c.2938C>T (p.Arg980Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
21570	NM_018136.5(ASPM):c.2967G>A (p.Trp989Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
21574	NM_018136.5(ASPM):c.3188T>G (p.Leu1063Ter)	ASPM	Pathogenic	criteria provided, single submitter
21606	NM_018136.5(ASPM):c.7782_7783del (p.Lys2595fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
21635	NM_018136.5(ASPM):c.9730C>T (p.Arg3244Ter)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
694714	NM_018136.5(ASPM):c.5863dup (p.Gln1955fs)	ASPM	Pathogenic	criteria provided, single submitter
694722	NM_018136.5(ASPM):c.8200_8201del (p.Asn2734fs)	ASPM	Pathogenic	criteria provided, single submitter
1817	NM_018451.5(CPAP):c.18del (p.Ser7fs)	CPAP	Pathogenic	criteria provided, multiple submitters, no conflicts
4533324	NM_018451.5(CPAP):c.3947C>A (p.Thr1316Lys)	CPAP	Pathogenic	criteria provided, single submitter
208150	NC_000008.10:g.(6060654_6061169)_(6310738_6317266)del	LOC129999780	Pathogenic	no assertion criteria provided
3456	NC_000008.10:g.(?6264113)(6296618_6299587)del	LOC129999781	Pathogenic	no assertion criteria provided
1180736	NM_024596.5(MCPH1):c.321del (p.Lys107fs)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158830	NM_024596.5(MCPH1):c.1869_1870del (p.Ser623_Cys624insTer)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705328	NM_024596.5(MCPH1):c.477del (p.Ser159_Leu160insTer)	MCPH1	Pathogenic	criteria provided, single submitter
2850164	NM_024596.5(MCPH1):c.733G>T (p.Gly245Ter)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2868001	NM_024596.5(MCPH1):c.76_77del (p.Lys26fs)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2879442	NM_024596.5(MCPH1):c.826_829del (p.Ser276fs)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2977643	NM_024596.5(MCPH1):c.571del (p.Ser191fs)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30639	NM_024596.5(MCPH1):c.566dup (p.Asn189fs)	MCPH1	Pathogenic	criteria provided, multiple submitters, no conflicts
30640	NM_024596.5(MCPH1):c.147C>G (p.His49Gln)	MCPH1	Pathogenic	no assertion criteria provided
30641	NM_024596.5(MCPH1):c.215C>T (p.Ser72Leu)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30642	NM_024596.5(MCPH1):c.302C>G (p.Ser101Ter)	MCPH1	Pathogenic	criteria provided, single submitter
3454	NM_024596.5(MCPH1):c.74C>G (p.Ser25Ter)	MCPH1	Pathogenic	criteria provided, single submitter
3455	NM_024596.5(MCPH1):c.427dup (p.Thr143fs)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3765887	NM_024596.5(MCPH1):c.115-1G>A	MCPH1	Pathogenic	criteria provided, single submitter
435838	NM_024596.5(MCPH1):c.22+2_22+4del	MCPH1	Pathogenic	criteria provided, single submitter
523934	NM_024596.5(MCPH1):c.321dup (p.Arg108fs)	MCPH1	Pathogenic	criteria provided, multiple submitters, no conflicts
586140	NM_024596.5(MCPH1):c.1625T>G (p.Leu542Ter)	MCPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
916000	GRCh37/hg19 8p23.2-23.1(chr8:6160874-6500521)	MCPH1	Pathogenic	no assertion criteria provided
916001	GRCh37/hg19 8p23.1(chr8:6261036-6312712)	MCPH1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
MCPH1	Definitive	Autosomal recessive	microcephaly 1, primary, autosomal recessive	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCPH1	Orphanet:2512	Autosomal recessive primary microcephaly
CPAP	Orphanet:2512	Autosomal recessive primary microcephaly
CPAP	Orphanet:808	Seckel syndrome
ASPM	Orphanet:2512	Autosomal recessive primary microcephaly
WDR62	Orphanet:2512	Autosomal recessive primary microcephaly
ANGPT2	Orphanet:363999	Non-immune hydrops fetalis

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MCPH1	HGNC:6954	ENSG00000147316	Q8NEM0	Microcephalin	gencc,clinvar
RNF17	HGNC:10060	ENSG00000132972	Q9BXT8	RING finger protein 17	clinvar
CPAP	HGNC:17272	ENSG00000151849	Q9HC77	Centrosomal P4.1-associated protein	clinvar
ASPM	HGNC:19048	ENSG00000066279	Q8IZT6	Abnormal spindle-like microcephaly-associated protein	clinvar
WDR62	HGNC:24502	ENSG00000075702	O43379	WD repeat-containing protein 62	clinvar
ANGPT2	HGNC:485	ENSG00000091879	O15123	Angiopoietin-2	clinvar
MCPH1-AS1	HGNC:51655	ENSG00000249898		MCPH1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCPH1	Microcephalin	Implicated in chromosome condensation and DNA damage induced cellular responses.
RNF17	RING finger protein 17	Seems to be involved in regulation of transcriptional activity of MYC.
CPAP	Centrosomal P4.1-associated protein	Plays an important role in cell division and centrosome function by participating in centriole duplication.
ASPM	Abnormal spindle-like microcephaly-associated protein	Involved in mitotic spindle regulation and coordination of mitotic processes.
WDR62	WD repeat-containing protein 62	Required for cerebral cortical development.
ANGPT2	Angiopoietin-2	Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 4 · Druggable fraction: 0.14

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
Antibody/Immunoglobulin	1	4.2×	0.626
Scaffold/PPI	1	2.5×	0.626
Transcription factor	1	1.2×	0.626
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCPH1	Other/Unknown	no		BRCT_dom, Microcephalin-like, Microcephalin_mammal
RNF17	Transcription factor	no		Znf_RING, Tudor, Znf_RING_CS
CPAP	Other/Unknown	no		CENPJ_C_dom, TCP10L/CENPJ, Tcp10_C_sf
ASPM	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, CH_dom, ARM-like
WDR62	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
ANGPT2	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_C_1, Fibrinogen_CS
MCPH1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	3
right testis	2
oocyte	2
calcaneal tendon	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
sperm	1
ventricular zone	1
left testis	1
testis	1
popliteal artery	1
tendon of biceps brachii	1
tibial artery	1
buccal mucosa cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCPH1	204	ubiquitous	marker	secondary oocyte, ganglionic eminence, calcaneal tendon
RNF17	142	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis
CPAP	246	ubiquitous	marker	sperm, left lobe of thyroid gland, right lobe of thyroid gland
ASPM	176	ubiquitous	marker	oocyte, ventricular zone, secondary oocyte
WDR62	211	ubiquitous	marker	left testis, right testis, testis
ANGPT2	219	broad	marker	tendon of biceps brachii, popliteal artery, tibial artery
MCPH1-AS1	167	ubiquitous	yes	buccal mucosa cell, oocyte, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASPM	2,949
CPAP	2,242
ANGPT2	2,065
MCPH1	1,499
WDR62	1,414
RNF17	1,108
MCPH1-AS1	0

Intra-cohort edges

A	B	Sources
ASPM	CPAP	string_interaction
ASPM	MCPH1	string_interaction
ASPM	WDR62	string_interaction
CPAP	MCPH1	string_interaction
CPAP	WDR62	string_interaction
MCPH1	WDR62	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCPH1	Q8NEM0	9
ANGPT2	O15123	7
CPAP	Q9HC77	6
RNF17	Q9BXT8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WDR62	O43379	61.19
ASPM	Q8IZT6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 7 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tie2 Signaling	1	200.3×	0.038	ANGPT2
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	173.0×	0.038	CPAP
Mitotic Prophase	1	122.8×	0.038	MCPH1
Loss of Nlp from mitotic centrosomes	1	52.9×	0.038	CPAP
Loss of proteins required for interphase microtubule organization from the centrosome	1	52.9×	0.038	CPAP
Condensation of Prophase Chromosomes	1	52.1×	0.038	MCPH1
AURKA Activation by TPX2	1	50.8×	0.038	CPAP
Recruitment of mitotic centrosome proteins and complexes	1	45.3×	0.038	CPAP
Regulation of PLK1 Activity at G2/M Transition	1	42.3×	0.038	CPAP
Recruitment of NuMA to mitotic centrosomes	1	38.8×	0.038	CPAP
Anchoring of the basal body to the plasma membrane	1	37.7×	0.038	CPAP
Cell surface interactions at the vascular wall	1	31.7×	0.042	ANGPT2
M Phase	1	22.0×	0.055	MCPH1
Cell Cycle, Mitotic	1	16.1×	0.070	MCPH1
Hemostasis	1	12.0×	0.081	ANGPT2
Cell Cycle	1	12.0×	0.081	MCPH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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 centrosome cycle	2	624.1×	1e-04	MCPH1, WDR62
cerebral cortex development	3	102.8×	1e-04	MCPH1, ASPM, WDR62
centriole replication	2	244.2×	6e-04	CPAP, WDR62
neuronal stem cell population maintenance	2	224.7×	6e-04	MCPH1, ASPM
positive regulation of neuroblast proliferation	2	193.7×	6e-04	ASPM, WDR62
astral microtubule nucleation	1	2808.7×	0.003	CPAP
negative regulation of asymmetric cell division	1	2808.7×	0.003	ASPM
negative regulation of positive chemotaxis	1	2808.7×	0.003	ANGPT2
forebrain neuroblast division	1	1404.3×	0.005	ASPM
regulation of chromosome condensation	1	1404.3×	0.005	MCPH1
meiotic spindle assembly	1	936.2×	0.007	ASPM
centriole elongation	1	702.2×	0.008	CPAP
glomerulus vasculature development	1	702.2×	0.008	ANGPT2
positive regulation of centriole replication	1	561.7×	0.008	CPAP
Tie signaling pathway	1	561.7×	0.008	ANGPT2
spindle localization	1	561.7×	0.008	ASPM
positive regulation of coagulation	1	468.1×	0.008	ANGPT2
maintenance of centrosome location	1	468.1×	0.008	ASPM
positive regulation of establishment of protein localization	1	468.1×	0.008	CPAP
asymmetric cell division	1	401.2×	0.008	ASPM
positive regulation of centriole elongation	1	401.2×	0.008	CPAP
positive regulation of spindle assembly	1	351.1×	0.009	CPAP
positive regulation of non-motile cilium assembly	1	312.1×	0.010	CPAP
regulation of centriole replication	1	280.9×	0.010	CPAP
negative regulation of cell-substrate adhesion	1	175.5×	0.016	ANGPT2
spindle organization	1	165.2×	0.016	ASPM
positive regulation of neuron migration	1	165.2×	0.016	WDR62
maternal process involved in female pregnancy	1	156.0×	0.016	ANGPT2
microtubule polymerization	1	147.8×	0.016	CPAP
regulation of mitotic spindle organization	1	140.4×	0.017	CPAP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 1 of 7 evidence-associated genes (14%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MCPH1	0	0
RNF17	0	0
CPAP	0	0
ASPM	0	0
WDR62	0	0
ANGPT2	0	0
MCPH1-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	1	ASPM
E	Difficult family or no structure, no drug	6	MCPH1, RNF17, CPAP, WDR62, ANGPT2, MCPH1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MCPH1	0	—
RNF17	0	—
CPAP	0	—
ASPM	0	—
WDR62	0	—
ANGPT2	0	—
MCPH1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.