Complex cortical dysplasia with other brain malformations 3

Summary

Complex cortical dysplasia with other brain malformations 3 (MONDO:0014170) is a disease caused by KIF2A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KIF2A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complex cortical dysplasia with other brain malformations 3
Mondo ID	MONDO:0014170
OMIM	615411
DOID	DOID:0090134
UMLS	C3809414
MedGen	815744
Is cancer (heuristic)	no

Also known as: CDCBM3 · complex cortical dysplasia with other brain malformations caused by mutation in KIF2A · complex cortical dysplasia with other brain malformations type 3 · cortical dysplasia, complex, with other brain malformations 3 · cortical dysplasia, Complex, with Other brain malformations type 3 · KIF2A complex cortical dysplasia with other brain malformations

Data availability: 26 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › complex cortical dysplasia with other brain malformations › complex cortical dysplasia with other brain malformations 3

Related subtypes (11): complex cortical dysplasia with other brain malformations 7, polymicrogyria with optic nerve hypoplasia, complex cortical dysplasia with other brain malformations 1, complex cortical dysplasia with other brain malformations 2, complex cortical dysplasia with other brain malformations 4, complex cortical dysplasia with other brain malformations 5, complex cortical dysplasia with other brain malformations 6, cortical dysplasia, complex, with other brain malformations 9, cortical dysplasia, complex, with other brain malformations 10, cortical dysplasia, complex, with other brain malformations 11, cortical dysplasia, complex, with other brain malformations 12

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

26 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 3 benign/likely benign, 3 pathogenic, 2 likely pathogenic, 2 benign, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
435642	NM_001098511.3(KIF2A):c.959C>T (p.Thr320Ile)	KIF2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65400	NM_001098511.3(KIF2A):c.961C>G (p.His321Asp)	KIF2A	Pathogenic	no assertion criteria provided
65401	NM_001098511.3(KIF2A):c.950G>A (p.Ser317Asn)	KIF2A	Pathogenic	criteria provided, multiple submitters, no conflicts
800959	NM_001098511.3(KIF2A):c.283C>T (p.Arg95Ter)	KIF2A	Pathogenic	no assertion criteria provided
1031823	NM_001098511.3(KIF2A):c.217G>A (p.Glu73Lys)	KIF2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
584429	NM_001098511.3(KIF2A):c.938G>A (p.Gly313Glu)	KIF2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426100	NM_001098511.3(KIF2A):c.1064A>G (p.Tyr355Cys)	KIF2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1948389	NM_001098511.3(KIF2A):c.1810A>T (p.Ile604Leu)	KIF2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2433148	NM_001098511.3(KIF2A):c.1760+5A>G	KIF2A	Uncertain significance	criteria provided, single submitter
2433149	NM_001098511.3(KIF2A):c.2000G>A (p.Arg667Lys)	KIF2A	Uncertain significance	criteria provided, single submitter
2627779	NM_001098511.3(KIF2A):c.1246A>G (p.Ile416Val)	KIF2A	Uncertain significance	no assertion criteria provided
2664183	NM_001098511.3(KIF2A):c.224G>A (p.Ser75Asn)	KIF2A	Uncertain significance	criteria provided, single submitter
3068009	NM_001098511.3(KIF2A):c.334G>A (p.Val112Met)	KIF2A	Uncertain significance	criteria provided, single submitter
3234930	NM_001098511.3(KIF2A):c.454C>T (p.Pro152Ser)	KIF2A	Uncertain significance	criteria provided, single submitter
3256899	NM_001098511.3(KIF2A):c.1388G>A (p.Arg463Lys)	KIF2A	Uncertain significance	criteria provided, single submitter
3893686	NM_001098511.3(KIF2A):c.1432G>C (p.Gly478Arg)	KIF2A	Uncertain significance	criteria provided, single submitter
4278040	NM_001098511.3(KIF2A):c.1297T>G (p.Ser433Ala)	KIF2A	Uncertain significance	criteria provided, single submitter
4846836	NM_001098511.3(KIF2A):c.458-11T>G	KIF2A	Uncertain significance	criteria provided, single submitter
930378	NM_001098511.3(KIF2A):c.82A>G (p.Met28Val)	KIF2A	Uncertain significance	criteria provided, single submitter
977394	NM_001098511.3(KIF2A):c.907G>A (p.Glu303Lys)	KIF2A	Uncertain significance	criteria provided, single submitter
2442132	NM_001098511.3(KIF2A):c.1A>G (p.Met1Val)	LOC129993961	Uncertain significance	criteria provided, single submitter
1258049	NM_001098511.3(KIF2A):c.1027+21A>T	KIF2A	Benign	criteria provided, multiple submitters, no conflicts
1585279	NM_001098511.3(KIF2A):c.35G>A (p.Gly12Glu)	KIF2A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
380829	NM_001098511.3(KIF2A):c.65-20T>C	KIF2A	Benign	criteria provided, multiple submitters, no conflicts
506410	NM_001098511.3(KIF2A):c.2044G>A (p.Ala682Thr)	KIF2A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
523636	NM_001098511.3(KIF2A):c.382T>C (p.Ser128Pro)	KIF2A	Benign/Likely 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
KIF2A	Strong	Autosomal dominant	complex cortical dysplasia with other brain malformations 3	3

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
KIF2A	HGNC:6318	ENSG00000068796	O00139	Kinesin-like protein KIF2A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF2A	Kinesin-like protein KIF2A	Plus end-directed microtubule-dependent motor required for normal brain development.

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)
KIF2A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

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
corpus callosum	1
cortical plate	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF2A	279	ubiquitous	marker	cortical plate, corpus callosum, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF2A	2,208

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF2A	O00139	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
Amplification of signal from the kinetochores	1	196.9×	0.024	KIF2A
Kinesins	1	178.4×	0.024	KIF2A
Mitotic Spindle Checkpoint	1	158.6×	0.024	KIF2A
Golgi-to-ER retrograde transport	1	132.8×	0.024	KIF2A
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	116.5×	0.024	KIF2A
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.024	KIF2A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	104.8×	0.024	KIF2A
Mitotic Metaphase and Anaphase	1	96.8×	0.024	KIF2A
Mitotic Anaphase	1	96.8×	0.024	KIF2A
EML4 and NUDC in mitotic spindle formation	1	92.8×	0.024	KIF2A
MHC class II antigen presentation	1	89.2×	0.024	KIF2A
Cell Cycle Checkpoints	1	88.5×	0.024	KIF2A
Resolution of Sister Chromatid Cohesion	1	86.5×	0.024	KIF2A
RHO GTPases Activate Formins	1	77.7×	0.024	KIF2A
Mitotic Prometaphase	1	69.2×	0.024	KIF2A
RHO GTPase Effectors	1	68.0×	0.024	KIF2A
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.024	KIF2A
M Phase	1	66.0×	0.024	KIF2A
Separation of Sister Chromatids	1	60.7×	0.025	KIF2A
Cell Cycle, Mitotic	1	48.2×	0.030	KIF2A
Membrane Trafficking	1	37.1×	0.033	KIF2A
Hemostasis	1	36.0×	0.033	KIF2A
Cell Cycle	1	36.0×	0.033	KIF2A
Vesicle-mediated transport	1	34.8×	0.033	KIF2A
Signaling by Rho GTPases	1	34.2×	0.033	KIF2A
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.033	KIF2A
Adaptive Immune System	1	29.8×	0.036	KIF2A
Immune System	1	13.0×	0.080	KIF2A
Signal Transduction	1	10.2×	0.098	KIF2A

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
microtubule depolymerization	1	1053.2×	0.008	KIF2A
mitotic spindle assembly	1	343.9×	0.008	KIF2A
microtubule-based movement	1	295.6×	0.008	KIF2A
mitotic spindle organization	1	271.8×	0.008	KIF2A
regulation of cell migration	1	157.5×	0.011	KIF2A
microtubule cytoskeleton organization	1	121.2×	0.012	KIF2A
cell division	1	46.2×	0.025	KIF2A
nervous system development	1	45.9×	0.025	KIF2A
cell differentiation	1	29.1×	0.034	KIF2A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIF2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KIF2A	6	Binding:6

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	KIF2A

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)
KIF2A	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.