Complex cortical dysplasia with other brain malformations 5

Summary

Complex cortical dysplasia with other brain malformations 5 (MONDO:0014337) is a disease caused by TUBB2A (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TUBB2A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complex cortical dysplasia with other brain malformations 5
Mondo ID	MONDO:0014337
OMIM	615763
DOID	DOID:0090135
UMLS	C3810407
MedGen	816737
GARD	0027859
Is cancer (heuristic)	no

Also known as: CDCBM5 · complex cortical dysplasia with other brain malformations caused by mutation in TUBB2A · complex cortical dysplasia with other brain malformations type 5 · cortical dysplasia, complex, with other brain malformations 5 · cortical dysplasia, Complex, with Other brain malformations type 5 · TUBB2A complex cortical dysplasia with other brain malformations · TUBB2A-related tubulinopathy

Data availability: 38 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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 5

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 3, complex cortical dysplasia with other brain malformations 4, 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

38 retrieved; paginated sample, class counts are floors:

11 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 7 likely pathogenic, 7 uncertain significance, 2 pathogenic, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
265284	NM_001069.3(TUBB2A):c.533C>T (p.Thr178Met)	BPHL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127100	NM_001069.3(TUBB2A):c.741C>G (p.Asn247Lys)	TUBB2A	Pathogenic	criteria provided, single submitter
1929379	NM_001069.3(TUBB2A):c.689C>T (p.Ser230Leu)	TUBB2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212495	NM_001069.3(TUBB2A):c.1033A>T (p.Ile345Phe)	TUBB2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2428890	NM_001069.3(TUBB2A):c.785G>A (p.Arg262His)	TUBB2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072027	NM_001069.3(TUBB2A):c.286G>A (p.Gly96Arg)	TUBB2A	Pathogenic	criteria provided, single submitter
421613	NM_001069.3(TUBB2A):c.394G>A (p.Gly132Ser)	TUBB2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
421739	NM_001069.3(TUBB2A):c.292G>A (p.Gly98Arg)	TUBB2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449113	NM_001069.3(TUBB2A):c.580G>A (p.Glu194Lys)	TUBB2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
975997	NM_001069.3(TUBB2A):c.292G>C (p.Gly98Arg)	TUBB2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1031017	NM_001069.3(TUBB2A):c.1073C>T (p.Pro358Leu)	TUBB2A	Likely pathogenic	criteria provided, single submitter
1065443	NM_001069.3(TUBB2A):c.1072C>A (p.Pro358Thr)	TUBB2A	Likely pathogenic	criteria provided, single submitter
1213605	NM_001069.3(TUBB2A):c.967A>C (p.Met323Leu)	TUBB2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685468	NM_001069.3(TUBB2A):c.148T>C (p.Tyr50His)	TUBB2A	Likely pathogenic	criteria provided, single submitter
3778745	NM_001069.3(TUBB2A):c.620T>C (p.Leu207Pro)	TUBB2A	Likely pathogenic	criteria provided, single submitter
3897572	NM_001069.3(TUBB2A):c.1204G>C (p.Gly402Arg)	TUBB2A	Likely pathogenic	criteria provided, single submitter
800924	NM_001069.3(TUBB2A):c.1178C>T (p.Ala393Val)	TUBB2A	Likely pathogenic	no assertion criteria provided
1320068	NM_001069.3(TUBB2A):c.5G>A (p.Arg2His)	LOC129995635	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127101	NM_001069.3(TUBB2A):c.743C>T (p.Ala248Val)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2100268	NM_001069.3(TUBB2A):c.875A>G (p.Gln292Arg)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2124428	NM_001069.3(TUBB2A):c.577G>A (p.Val193Met)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217024	NM_001069.3(TUBB2A):c.872A>C (p.Gln291Pro)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3343922	NM_001069.3(TUBB2A):c.853A>C (p.Thr285Pro)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372867	NM_001069.3(TUBB2A):c.602C>G (p.Ser201Cys)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
382096	NM_001069.3(TUBB2A):c.1172G>A (p.Arg391His)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
437124	NM_001069.3(TUBB2A):c.1163T>C (p.Met388Thr)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521900	NM_001069.3(TUBB2A):c.1171C>T (p.Arg391Cys)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546138	NM_001069.3(TUBB2A):c.728C>T (p.Pro243Leu)	TUBB2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319919	NM_001069.3(TUBB2A):c.928T>C (p.Tyr310His)	TUBB2A	Uncertain significance	no assertion criteria provided
1995789	NM_001069.3(TUBB2A):c.266A>G (p.Asn89Ser)	TUBB2A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TUBB2A	Definitive	Autosomal dominant	complex cortical dysplasia with other brain malformations 5	4

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
TUBB2A	HGNC:12412	ENSG00000137267	Q13885	Tubulin beta-2A chain	gencc,clinvar
BPHL	HGNC:1094	ENSG00000137274	Q86WA6	Serine hydrolase BPHL	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB2A	Tubulin beta-2A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
BPHL	Serine hydrolase BPHL	Specific alpha-amino acid ester serine hydrolase that prefers small, hydrophobic, and aromatic side chains and does not have a stringent requirement for the leaving group other than preferring a primary alcohol.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBB2A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
BPHL	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold

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
dorsal root ganglion	1
endothelial cell	1
pons	1
adult mammalian kidney	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB2A	293	ubiquitous	marker	endothelial cell, dorsal root ganglion, pons
BPHL	253	ubiquitous	marker	right lobe of liver, adult mammalian kidney, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB2A	5,621
BPHL	1,390

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BPHL	Q86WA6	4
TUBB2A	Q13885	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 89. 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
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	271.9×	0.031	TUBB2A
Transport of connexons to the plasma membrane	1	271.9×	0.031	TUBB2A
Gap junction trafficking and regulation	1	237.9×	0.031	TUBB2A
Gap junction trafficking	1	237.9×	0.031	TUBB2A
Post-chaperonin tubulin folding pathway	1	237.9×	0.031	TUBB2A
Formation of tubulin folding intermediates by CCT/TriC	1	211.5×	0.031	TUBB2A
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	203.9×	0.031	TUBB2A
Prefoldin mediated transfer of substrate to CCT/TriC	1	196.9×	0.031	TUBB2A
Activation of AMPK downstream of NMDARs	1	190.3×	0.031	TUBB2A
RHO GTPases activate IQGAPs	1	173.0×	0.031	TUBB2A
Sealing of the nuclear envelope (NE) by ESCRT-III	1	173.0×	0.031	TUBB2A
HCMV Infection	1	163.1×	0.031	TUBB2A
Chaperonin-mediated protein folding	1	150.3×	0.031	TUBB2A
Gap junction assembly	1	146.4×	0.031	TUBB2A
Nuclear Envelope (NE) Reassembly	1	146.4×	0.031	TUBB2A
Selective autophagy	1	139.3×	0.031	TUBB2A
Protein folding	1	129.8×	0.031	TUBB2A
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.031	TUBB2A
Cargo trafficking to the periciliary membrane	1	124.1×	0.031	TUBB2A
Aggrephagy	1	124.1×	0.031	TUBB2A
Carboxyterminal post-translational modifications of tubulin	1	119.0×	0.031	TUBB2A
Recycling pathway of L1	1	112.0×	0.031	TUBB2A
Phase I - Functionalization of compounds	1	109.8×	0.031	BPHL
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.031	TUBB2A
Post NMDA receptor activation events	1	102.0×	0.031	TUBB2A
Intraflagellar transport	1	100.2×	0.031	TUBB2A
Antimicrobial mechanism of IFN-stimulated genes	1	98.5×	0.031	TUBB2A
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.031	TUBB2A
Activation of NMDA receptors and postsynaptic events	1	92.1×	0.031	TUBB2A
Signaling by Hedgehog	1	92.1×	0.031	TUBB2A

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
homocysteine metabolic process	1	936.2×	0.009	BPHL
amino acid metabolic process	1	401.2×	0.010	BPHL
response to toxic substance	1	105.3×	0.016	BPHL
cerebral cortex development	1	102.8×	0.016	TUBB2A
xenobiotic metabolic process	1	74.6×	0.016	BPHL
mitotic cell cycle	1	66.9×	0.016	TUBB2A
neuron migration	1	66.9×	0.016	TUBB2A
microtubule cytoskeleton organization	1	60.6×	0.016	TUBB2A

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
TUBB2A	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB2A	21	4
BPHL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB2A
VINBLASTINE	4	TUBB2A
LEVOFLOXACIN ANHYDROUS	4	TUBB2A
DOCETAXEL	4	TUBB2A
NOSCAPINE	4	TUBB2A
VINBLASTINE SULFATE	4	TUBB2A
PACLITAXEL	4	TUBB2A
LEVOFLOXACIN	4	TUBB2A
VINORELBINE	4	TUBB2A
TIRBANIBULIN	4	TUBB2A
PODOFILOX	4	TUBB2A
VINCRISTINE	4	TUBB2A
DOCETAXEL ANHYDROUS	4	TUBB2A
PATUPILONE	3	TUBB2A
ABT-751	2	TUBB2A
MAYTANSINE	2	TUBB2A
DOLASTATIN-10	2	TUBB2A
INDIBULIN	2	TUBB2A
PARBENDAZOLE	2	TUBB2A
NOCODAZOLE	2	TUBB2A
COMBRETASTATIN	1	TUBB2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB2A	1,758	Binding:1718, Functional:34, ADMET:6
BPHL	4	Binding:4

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBB2A	1,758

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

21 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)
COLCHICINE	4	TUBB2A
VINBLASTINE	4	TUBB2A
LEVOFLOXACIN ANHYDROUS	4	TUBB2A
DOCETAXEL	4	TUBB2A
NOSCAPINE	4	TUBB2A
VINBLASTINE SULFATE	4	TUBB2A
PACLITAXEL	4	TUBB2A
LEVOFLOXACIN	4	TUBB2A
VINORELBINE	4	TUBB2A
TIRBANIBULIN	4	TUBB2A
PODOFILOX	4	TUBB2A
VINCRISTINE	4	TUBB2A
DOCETAXEL ANHYDROUS	4	TUBB2A
PATUPILONE	3	TUBB2A
ABT-751	2	TUBB2A
MAYTANSINE	2	TUBB2A
DOLASTATIN-10	2	TUBB2A
INDIBULIN	2	TUBB2A
PARBENDAZOLE	2	TUBB2A
NOCODAZOLE	2	TUBB2A
COMBRETASTATIN	1	TUBB2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB2A
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	BPHL

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)
BPHL	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.