TUBB3-related tubulinopathy

Summary

TUBB3-related tubulinopathy (MONDO:0100154) is a disease caused by TUBB (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TUBB (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	TUBB3-related tubulinopathy
Mondo ID	MONDO:0100154
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › tubulinopathy › TUBB3-related tubulinopathy

Related subtypes (3): complex cortical dysplasia with other brain malformations 5, tubulinopathy-associated dysgyria, Uner Tan Syndrome

Subtypes (1): fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement

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

6 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
219255	NM_006086.4(TUBB3):c.211G>A (p.Gly71Arg)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219256	NM_006086.4(TUBB3):c.785G>A (p.Arg262His)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
384329	NM_006086.4(TUBB3):c.862G>A (p.Glu288Lys)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6966	NM_006086.4(TUBB3):c.1249G>A (p.Asp417Asn)	TUBB3	Pathogenic	criteria provided, multiple submitters, no conflicts
989267	NM_006086.4(TUBB3):c.730G>T (p.Gly244Cys)	TUBB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3061817	NM_006086.4(TUBB3):c.371G>C (p.Cys124Ser)	TUBB3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
TUBB	Definitive	Autosomal dominant	TUBB3-related tubulinopathy	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB	Orphanet:2505	Multiple benign circumferential skin creases on limbs
TUBB3	Orphanet:300570	Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation
TUBB3	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBB3	Orphanet:467166	Tubulinopathy-associated dysgyria

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
TUBB	HGNC:20778	ENSG00000196230	P07437	Tubulin beta chain	gencc
TUBB3	HGNC:20772	ENSG00000258947	Q13509	Tubulin beta-3 chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB	Tubulin beta chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
TUBB3	Tubulin beta-3 chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.

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)
TUBB	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
TUBB3	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase

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
cortical plate	2
ganglionic eminence	2
ventricular zone	1
embryo	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB	133	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
TUBB3	144	ubiquitous	marker	cortical plate, ganglionic eminence, embryo

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB3	6,797
TUBB	1,512

Intra-cohort edges

A	B	Sources
TUBB	TUBB3	intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBB3	Q13509	28
TUBB	P07437	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 97. 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
Mitotic G2-G2/M phases	2	126.9×	0.002	TUBB3, TUBB
G2/M Transition	2	126.9×	0.002	TUBB3, TUBB
Recruitment of NuMA to mitotic centrosomes	2	116.5×	0.002	TUBB3, TUBB
Cilium Assembly	2	108.8×	0.002	TUBB3, TUBB
Mitotic Prometaphase	2	69.2×	0.003	TUBB3, TUBB
Organelle biogenesis and maintenance	2	66.0×	0.003	TUBB3, TUBB
M Phase	2	66.0×	0.003	TUBB3, TUBB
Cell Cycle, Mitotic	2	48.2×	0.005	TUBB3, TUBB
Cell Cycle	2	36.0×	0.008	TUBB3, TUBB
Viral Infection Pathways	2	30.8×	0.010	TUBB3, TUBB
Infectious disease	2	24.8×	0.014	TUBB3, TUBB
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	271.9×	0.023	TUBB3
Transport of connexons to the plasma membrane	1	271.9×	0.023	TUBB3
Gap junction trafficking and regulation	1	237.9×	0.023	TUBB3
Gap junction trafficking	1	237.9×	0.023	TUBB3
Post-chaperonin tubulin folding pathway	1	237.9×	0.023	TUBB3
Formation of tubulin folding intermediates by CCT/TriC	1	211.5×	0.023	TUBB3
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	203.9×	0.023	TUBB3
Prefoldin mediated transfer of substrate to CCT/TriC	1	196.9×	0.023	TUBB3
Activation of AMPK downstream of NMDARs	1	190.3×	0.023	TUBB3
RHO GTPases activate IQGAPs	1	173.0×	0.023	TUBB3
Sealing of the nuclear envelope (NE) by ESCRT-III	1	173.0×	0.023	TUBB3
HCMV Infection	1	163.1×	0.023	TUBB3
Chaperonin-mediated protein folding	1	150.3×	0.023	TUBB3
Gap junction assembly	1	146.4×	0.023	TUBB3
Nuclear Envelope (NE) Reassembly	1	146.4×	0.023	TUBB3
Selective autophagy	1	139.3×	0.023	TUBB3
Protein folding	1	129.8×	0.023	TUBB3
Centrosome maturation	1	126.9×	0.023	TUBB
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.023	TUBB3

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
mitotic cell cycle	2	133.8×	4e-04	TUBB3, TUBB
microtubule cytoskeleton organization	2	121.2×	4e-04	TUBB3, TUBB
dorsal root ganglion development	1	1685.2×	0.002	TUBB3
odontoblast differentiation	1	1053.2×	0.003	TUBB
microtubule-based process	1	495.6×	0.004	TUBB
cytoskeleton-dependent intracellular transport	1	468.1×	0.004	TUBB
regulation of synapse organization	1	324.1×	0.005	TUBB
spindle assembly	1	221.7×	0.006	TUBB
natural killer cell mediated cytotoxicity	1	216.1×	0.006	TUBB
axon guidance	1	45.3×	0.024	TUBB3
cell division	1	23.1×	0.043	TUBB

Therapeutics

Drug target analysis

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

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
TUBB	COLCHICINE
TUBB3	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB	22	4
TUBB3	21	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB, TUBB3
VINBLASTINE	4	TUBB, TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB, TUBB3
DOCETAXEL	4	TUBB, TUBB3
NOSCAPINE	4	TUBB, TUBB3
VINBLASTINE SULFATE	4	TUBB, TUBB3
PACLITAXEL	4	TUBB, TUBB3
LEVOFLOXACIN	4	TUBB, TUBB3
VINORELBINE	4	TUBB, TUBB3
TIRBANIBULIN	4	TUBB, TUBB3
PODOFILOX	4	TUBB, TUBB3
VINCRISTINE	4	TUBB, TUBB3
DOCETAXEL ANHYDROUS	4	TUBB, TUBB3
PATUPILONE	3	TUBB, TUBB3
ABT-751	2	TUBB, TUBB3
MAYTANSINE	2	TUBB, TUBB3
DOLASTATIN-10	2	TUBB, TUBB3
INDIBULIN	2	TUBB, TUBB3
PARBENDAZOLE	2	TUBB, TUBB3
NOCODAZOLE	2	TUBB, TUBB3
MOLIBRESIB	2	TUBB
COMBRETASTATIN	1	TUBB, TUBB3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB3	1,781	Binding:1741, Functional:34, ADMET:6
TUBB	1,780	Binding:1740, Functional:34, ADMET:6

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBB	1,780
TUBB3	1,781

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

22 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	TUBB, TUBB3
VINBLASTINE	4	TUBB, TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB, TUBB3
DOCETAXEL	4	TUBB, TUBB3
NOSCAPINE	4	TUBB, TUBB3
VINBLASTINE SULFATE	4	TUBB, TUBB3
PACLITAXEL	4	TUBB, TUBB3
LEVOFLOXACIN	4	TUBB, TUBB3
VINORELBINE	4	TUBB, TUBB3
TIRBANIBULIN	4	TUBB, TUBB3
PODOFILOX	4	TUBB, TUBB3
VINCRISTINE	4	TUBB, TUBB3
DOCETAXEL ANHYDROUS	4	TUBB, TUBB3
PATUPILONE	3	TUBB, TUBB3
ABT-751	2	TUBB, TUBB3
MAYTANSINE	2	TUBB, TUBB3
DOLASTATIN-10	2	TUBB, TUBB3
INDIBULIN	2	TUBB, TUBB3
PARBENDAZOLE	2	TUBB, TUBB3
NOCODAZOLE	2	TUBB, TUBB3
MOLIBRESIB	2	TUBB
COMBRETASTATIN	1	TUBB, TUBB3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TUBB, TUBB3
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.