Microcephaly 21, primary, autosomal recessive

Summary

Microcephaly 21, primary, autosomal recessive (MONDO:0054804) is a disease caused by NCAPD2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NCAPD2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 21, primary, autosomal recessive
Mondo ID	MONDO:0054804
OMIM	617983
DOID	DOID:0051032
UMLS	C4693831
MedGen	1646916
GARD	0016278
Is cancer (heuristic)	no

Also known as: MCPH21

Data availability: 20 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 21, 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 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

20 retrieved; paginated sample, class counts are floors:

8 benign, 6 uncertain significance, 4 likely pathogenic, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
524202	NM_014865.4(NCAPD2):c.4120+2T>C	GAPDH	Pathogenic	criteria provided, single submitter
1339659	NM_014865.4(NCAPD2):c.2508del (p.Phe837fs)	NCAPD2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780009	NM_014865.4(NCAPD2):c.806_807del (p.Tyr269fs)	NCAPD2	Likely pathogenic	criteria provided, single submitter
4849400	NM_014865.4(NCAPD2):c.532C>T (p.Gln178Ter)	NCAPD2	Likely pathogenic	criteria provided, single submitter
4849449	NM_014865.4(NCAPD2):c.2761_2777delinsG (p.Phe921fs)	NCAPD2	Likely pathogenic	criteria provided, single submitter
546696	NM_014865.4(NCAPD2):c.1954+1G>A	NCAPD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030382	NM_014865.4(NCAPD2):c.1166C>T (p.Thr389Ile)	NCAPD2	Uncertain significance	criteria provided, single submitter
1030383	NM_014865.4(NCAPD2):c.1526A>G (p.Asn509Ser)	NCAPD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030435	NM_014865.4(NCAPD2):c.3830A>T (p.Glu1277Val)	NCAPD2	Uncertain significance	criteria provided, single submitter
2431533	NM_014865.4(NCAPD2):c.3054_3057del (p.Leu1019fs)	NCAPD2	Uncertain significance	criteria provided, single submitter
3342710	NM_014865.4(NCAPD2):c.2008C>T (p.Gln670Ter)	NCAPD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891811	NM_014865.4(NCAPD2):c.2542C>T (p.Arg848Ter)	NCAPD2	Uncertain significance	criteria provided, single submitter
1238523	NM_014865.4(NCAPD2):c.1920C>A (p.Ile640=)	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts
1321843	NM_014865.4(NCAPD2):c.127+27C>T	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts
1321844	NM_014865.4(NCAPD2):c.247C>G (p.Gln83Glu)	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts
1321845	NM_014865.4(NCAPD2):c.2566+30A>T	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts
1321846	NM_014865.4(NCAPD2):c.3300T>C (p.Arg1100=)	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts
1321847	NM_014865.4(NCAPD2):c.3483C>T (p.Asn1161=)	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts
1321848	NM_014865.4(NCAPD2):c.3573-13C>T	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts
1321849	NM_014865.4(NCAPD2):c.3801A>G (p.Val1267=)	NCAPD2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
NCAPD2	Strong	Autosomal recessive	microcephaly 21, primary, autosomal recessive	3

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
NCAPD2	HGNC:24305	ENSG00000010292	Q15021	Condensin complex subunit 1	gencc,clinvar
GAPDH	HGNC:4141	ENSG00000111640	P04406	Glyceraldehyde-3-phosphate dehydrogenase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NCAPD2	Condensin complex subunit 1	Regulatory subunit of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes.
GAPDH	Glyceraldehyde-3-phosphate dehydrogenase	Catalyzes the conversion of D-glyceraldehyde 3-phosphate (G3P) into 3-phospho-D-glyceroyl phosphate in glycolysis and the reverse reaction in gluconeogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NCAPD2	Other/Unknown	no		Condensin_cplx_su1, ARM-like, ARM-type_fold
GAPDH	Enzyme (other)	yes	1.2.1.12	Glyceraldehyde-3-P_DH_1, GlycerAld_3-P_DH_NAD(P)-bd, GlycerAld_3-P_DH_cat

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
bone marrow cell	1
ganglionic eminence	1
ventricular zone	1
frontal pole	1
paraflocculus	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NCAPD2	215	ubiquitous	marker	ventricular zone, ganglionic eminence, bone marrow cell
GAPDH	314	ubiquitous	marker	pons, frontal pole, paraflocculus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NCAPD2	2,553
GAPDH	1,450

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GAPDH	P04406	21

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NCAPD2	Q15021	79.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Condensation of Prometaphase Chromosomes	1	519.1×	0.006	NCAPD2
Gluconeogenesis	1	219.6×	0.007	GAPDH
Glycolysis	1	142.8×	0.007	GAPDH

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
peptidyl-cysteine S-trans-nitrosylation	1	2808.7×	0.005	GAPDH
meiotic chromosome condensation	1	1404.3×	0.005	NCAPD2
positive regulation of chromosome condensation	1	1053.2×	0.005	NCAPD2
negative regulation of endopeptidase activity	1	842.6×	0.005	GAPDH
positive regulation of chromosome separation	1	842.6×	0.005	NCAPD2
obsolete killing by host of symbiont cells	1	702.2×	0.005	GAPDH
positive regulation of chromosome segregation	1	648.1×	0.005	NCAPD2
mitotic chromosome condensation	1	495.6×	0.006	NCAPD2
canonical glycolysis	1	351.1×	0.007	GAPDH
defense response to fungus	1	221.7×	0.010	GAPDH
positive regulation of type I interferon production	1	210.7×	0.010	GAPDH
glycolytic process	1	191.5×	0.010	GAPDH
regulation of macroautophagy	1	147.8×	0.011	GAPDH
positive regulation of cytokine production	1	135.9×	0.011	GAPDH
killing of cells of another organism	1	135.9×	0.011	GAPDH
cellular response to type II interferon	1	104.0×	0.014	GAPDH
negative regulation of translation	1	98.0×	0.014	GAPDH
neuron apoptotic process	1	92.6×	0.014	GAPDH
antimicrobial humoral immune response mediated by antimicrobial peptide	1	81.0×	0.015	GAPDH
microtubule cytoskeleton organization	1	60.6×	0.019	GAPDH
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.030	GAPDH
protein stabilization	1	33.4×	0.031	GAPDH
cell division	1	23.1×	0.043	NCAPD2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
GAPDH	ADENOSINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GAPDH	4	4
NCAPD2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE	4	GAPDH
MOLIBRESIB	2	GAPDH
OXIDOPAMINE	2	GAPDH
BAICALEIN	2	GAPDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GAPDH	90	Binding:90
NCAPD2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GAPDH	1.2.1.12	glyceraldehyde-3-phosphate dehydrogenase (phosphorylating)

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

4 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)
ADENOSINE	4	GAPDH
MOLIBRESIB	2	GAPDH
OXIDOPAMINE	2	GAPDH
BAICALEIN	2	GAPDH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GAPDH
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	NCAPD2

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)
NCAPD2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.