Microcephaly 6, primary, autosomal recessive

Summary

Microcephaly 6, primary, autosomal recessive (MONDO:0012029) is a disease caused by CPAP (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CPAP (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 154

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 6, primary, autosomal recessive
Mondo ID	MONDO:0012029
MeSH	C564247
OMIM	608393
DOID	DOID:0070290
UMLS	C1842109
MedGen	330770
GARD	0015431
Is cancer (heuristic)	no

Also known as: autosomal recessive primary microcephaly caused by mutation in CENPJ · CENPJ autosomal recessive primary microcephaly · MCPH6 · microcephaly 6, primary, autosomal recessive

Data availability: 154 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 with or without short stature › microcephaly 6 with or without short stature › microcephaly 6, primary, autosomal recessive

Related subtypes (1): Seckel syndrome 4

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

154 retrieved; paginated sample, class counts are floors:

71 uncertain significance, 31 conflicting classifications of pathogenicity, 15 benign, 10 pathogenic, 10 pathogenic/likely pathogenic, 9 benign/likely benign, 7 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032802	NM_018451.5(CPAP):c.2117_2118del (p.Asp705_Ser706insTer)	CPAP	Pathogenic	criteria provided, multiple submitters, no conflicts
158194	NM_018451.5(CPAP):c.1586C>G (p.Ser529Ter)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676662	NM_018451.5(CPAP):c.2863G>T (p.Glu955Ter)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1817	NM_018451.5(CPAP):c.18del (p.Ser7fs)	CPAP	Pathogenic	criteria provided, multiple submitters, no conflicts
1818	NM_018451.5(CPAP):c.3704A>T (p.Glu1235Val)	CPAP	Pathogenic	no assertion criteria provided
1819	NM_018451.5(CPAP):c.3243_3246del (p.Ser1081fs)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210661	NM_018451.5(CPAP):c.1969C>T (p.Gln657Ter)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429273	NM_018451.5(CPAP):c.505_506del (p.Gln169fs)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279750	NM_018451.5(CPAP):c.289dup (p.Thr97fs)	CPAP	Pathogenic	criteria provided, multiple submitters, no conflicts
280184	NM_018451.5(CPAP):c.1696C>T (p.Arg566Ter)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280927	NM_018451.5(CPAP):c.40C>T (p.Gln14Ter)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432139	NM_018451.5(CPAP):c.2872C>T (p.Arg958Ter)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688175	NM_018451.5(CPAP):c.3398_3399del (p.Leu1133fs)	CPAP	Pathogenic	criteria provided, single submitter
496762	NM_018451.5(CPAP):c.3586G>A (p.Asp1196Asn)	CPAP	Pathogenic	no assertion criteria provided
496814	NM_018451.5(CPAP):c.59G>A (p.Trp20Ter)	CPAP	Pathogenic	no assertion criteria provided
503611	NM_018451.5(CPAP):c.1132C>T (p.Arg378Ter)	CPAP	Pathogenic	criteria provided, multiple submitters, no conflicts
620160	NM_018451.5(CPAP):c.634G>T (p.Glu212Ter)	CPAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158211	NM_018451.5(CPAP):c.3448C>T (p.Gln1150Ter)	RNF17	Pathogenic	criteria provided, single submitter
18417	NM_018451.5(CPAP):c.3302-1G>C	RNF17	Pathogenic	criteria provided, single submitter
1975927	NM_018451.5(CPAP):c.3673del (p.Glu1225fs)	RNF17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679845	NM_018451.5(CPAP):c.265_266del (p.Gln89fs)	CPAP	Likely pathogenic	criteria provided, single submitter
4294006	NM_018451.5(CPAP):c.3673dup (p.Glu1225fs)	CPAP	Likely pathogenic	criteria provided, single submitter
4819892	NM_018451.5(CPAP):c.422del (p.Pro141fs)	CPAP	Likely pathogenic	criteria provided, single submitter
4845881	NM_018451.5(CPAP):c.723_734delinsC (p.Gln241fs)	CPAP	Likely pathogenic	criteria provided, single submitter
522642	NM_018451.5(CPAP):c.3893G>A (p.Arg1298Gln)	CPAP	Likely pathogenic	criteria provided, single submitter
977853	NM_018451.5(CPAP):c.1426C>T (p.Gln476Ter)	CPAP	Likely pathogenic	no assertion criteria provided
417856	NM_018451.5(CPAP):c.3367-1G>A	RNF17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
158192	NM_018451.5(CPAP):c.1410G>A (p.Pro470=)	CPAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158193	NM_018451.5(CPAP):c.1513G>A (p.Glu505Lys)	CPAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158196	NM_018451.5(CPAP):c.175A>G (p.Thr59Ala)	CPAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
CPAP	Definitive	Autosomal recessive	microcephaly 6 with or without short stature	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CPAP	Orphanet:2512	Autosomal recessive primary microcephaly
CPAP	Orphanet:808	Seckel syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CPAP	HGNC:17272	ENSG00000151849	Q9HC77	Centrosomal P4.1-associated protein	gencc,clinvar
RNF17	HGNC:10060	ENSG00000132972	Q9BXT8	RING finger protein 17	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CPAP	Centrosomal P4.1-associated protein	Plays an important role in cell division and centrosome function by participating in centriole duplication.
RNF17	RING finger protein 17	Seems to be involved in regulation of transcriptional activity of MYC.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CPAP	Other/Unknown	no		CENPJ_C_dom, TCP10L/CENPJ, Tcp10_C_sf
RNF17	Transcription factor	no		Znf_RING, Tudor, Znf_RING_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	1
right lobe of thyroid gland	1
sperm	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CPAP	246	ubiquitous	marker	sperm, left lobe of thyroid gland, right lobe of thyroid gland
RNF17	142	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CPAP	2,242
RNF17	1,108

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CPAP	Q9HC77	6
RNF17	Q9BXT8	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	519.1×	0.009	CPAP
Loss of Nlp from mitotic centrosomes	1	158.6×	0.009	CPAP
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.009	CPAP
AURKA Activation by TPX2	1	152.3×	0.009	CPAP
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.009	CPAP
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.009	CPAP
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.009	CPAP
Anchoring of the basal body to the plasma membrane	1	113.1×	0.009	CPAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
astral microtubule nucleation	1	8426.0×	0.002	CPAP
centriole elongation	1	2106.5×	0.003	CPAP
positive regulation of centriole replication	1	1685.2×	0.003	CPAP
positive regulation of establishment of protein localization	1	1404.3×	0.003	CPAP
positive regulation of centriole elongation	1	1203.7×	0.003	CPAP
positive regulation of spindle assembly	1	1053.2×	0.003	CPAP
positive regulation of non-motile cilium assembly	1	936.2×	0.003	CPAP
regulation of centriole replication	1	842.6×	0.003	CPAP
microtubule polymerization	1	443.5×	0.005	CPAP
regulation of mitotic spindle organization	1	421.3×	0.005	CPAP
centriole replication	1	366.4×	0.005	CPAP
microtubule nucleation	1	312.1×	0.005	CPAP
motile cilium assembly	1	290.6×	0.005	CPAP
positive regulation of receptor signaling pathway via JAK-STAT	1	216.1×	0.007	CPAP
positive regulation of G1/S transition of mitotic cell cycle	1	200.6×	0.007	CPAP
non-motile cilium assembly	1	145.3×	0.009	CPAP
smoothened signaling pathway	1	90.6×	0.013	CPAP
spermatid development	1	72.6×	0.015	RNF17
cilium assembly	1	36.8×	0.028	CPAP
cell division	1	23.1×	0.043	CPAP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
CPAP	0	0
RNF17	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CPAP, RNF17

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CPAP	0	—
RNF17	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.