Macrothrombocytopenia, isolated, 1, autosomal dominant

Summary

Macrothrombocytopenia, isolated, 1, autosomal dominant (MONDO:0800047) is a disease caused by TUBB1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TUBB1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 53

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	macrothrombocytopenia, isolated, 1, autosomal dominant
Mondo ID	MONDO:0800047
MeSH	C567747
OMIM	613112
DOID	DOID:0090102
UMLS	C5676892
MedGen	1811721
GARD	0018271
Is cancer (heuristic)	no

Also known as: autosomal dominant macrothrombocytopenia caused by mutation in TUBB1 · macrothrombocytopenia, autosomal dominant, TUBB1-related · MACTHC1 · TUBB1 autosomal dominant macrothrombocytopenia

Data availability: 53 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytopenia › inherited thrombocytopenia › autosomal dominant macrothrombocytopenia › macrothrombocytopenia, isolated, 1, autosomal dominant

Related subtypes (2): platelet-type bleeding disorder 15, macrothrombocytopenia, isolated, 2, autosomal dominant

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

53 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 17 conflicting classifications of pathogenicity, 5 likely pathogenic, 2 benign/likely benign, 1 likely benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703807	NM_030773.4(TUBB1):c.806G>A (p.Gly269Asp)	TUBB1	Pathogenic	criteria provided, single submitter
372810	NM_030773.4(TUBB1):c.779T>C (p.Phe260Ser)	TUBB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028901	NM_030773.4(TUBB1):c.57+1G>A	TUBB1	Likely pathogenic	criteria provided, single submitter
1684388	NM_030773.4(TUBB1):c.726C>G (p.Phe242Leu)	TUBB1	Likely pathogenic	no assertion criteria provided
1709749	NM_030773.4(TUBB1):c.166+1G>C	TUBB1	Likely pathogenic	criteria provided, single submitter
3391094	NM_030773.4(TUBB1):c.796_798del (p.Phe266del)	TUBB1	Likely pathogenic	criteria provided, single submitter
4077724	NM_030773.4(TUBB1):c.128_131delinsCCC (p.Gln43fs)	TUBB1	Likely pathogenic	criteria provided, single submitter
1338448	NM_030773.4(TUBB1):c.400C>T (p.Gln134Ter)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676726	NM_030773.4(TUBB1):c.388C>G (p.Leu130Val)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676730	NM_030773.4(TUBB1):c.167-7T>C	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1677273	NM_030773.4(TUBB1):c.1267C>T (p.Gln423Ter)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1684382	NM_030773.4(TUBB1):c.745G>C (p.Asp249His)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1698752	NM_030773.4(TUBB1):c.578T>C (p.Ile193Thr)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2138364	NM_030773.4(TUBB1):c.128_129delinsCC (p.Gln43Pro)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2634318	NM_030773.4(TUBB1):c.844C>T (p.Arg282Ter)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377103	NM_030773.4(TUBB1):c.1075C>T (p.Arg359Trp)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
425	NM_030773.4(TUBB1):c.952C>T (p.Arg318Trp)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
586966	NM_030773.4(TUBB1):c.35del (p.Cys12fs)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626929	NM_030773.4(TUBB1):c.326G>A (p.Gly109Glu)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627037	NM_030773.4(TUBB1):c.229C>T (p.Arg77Ter)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627071	NM_030773.4(TUBB1):c.436G>A (p.Gly146Arg)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627129	NM_030773.4(TUBB1):c.752G>A (p.Arg251His)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
988861	NM_030773.4(TUBB1):c.13G>A (p.Val5Ile)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
988877	NM_030773.4(TUBB1):c.1080dup (p.Leu361fs)	TUBB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1312767	NM_030773.4(TUBB1):c.965C>T (p.Ser322Phe)	TUBB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1328166	NM_030773.4(TUBB1):c.850C>T (p.Leu284Phe)	TUBB1	Uncertain significance	criteria provided, single submitter
1677272	NM_030773.4(TUBB1):c.1036C>T (p.Pro346Ser)	TUBB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1677274	NM_030773.4(TUBB1):c.319A>C (p.Thr107Pro)	TUBB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1684355	NM_030773.4(TUBB1):c.1199G>A (p.Ser400Asn)	TUBB1	Uncertain significance	no assertion criteria provided
1684360	NM_030773.4(TUBB1):c.-88G>C	TUBB1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
TUBB1	Definitive	Autosomal dominant	macrothrombocytopenia, isolated, 1, autosomal dominant	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB1	Orphanet:140957	Autosomal dominant macrothrombocytopenia

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
TUBB1	HGNC:16257	ENSG00000101162	Q9H4B7	Tubulin beta-1 chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB1	Tubulin beta-1 chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.

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)
TUBB1	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase

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
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB1	140	tissue_specific	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB1	4,106

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB1	Q9H4B7	90.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. 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
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.016	TUBB1
Transport of connexons to the plasma membrane	1	543.8×	0.016	TUBB1
Gap junction trafficking and regulation	1	475.8×	0.016	TUBB1
Gap junction trafficking	1	475.8×	0.016	TUBB1
Post-chaperonin tubulin folding pathway	1	475.8×	0.016	TUBB1
Formation of tubulin folding intermediates by CCT/TriC	1	423.0×	0.016	TUBB1
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.016	TUBB1
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.016	TUBB1
Activation of AMPK downstream of NMDARs	1	380.7×	0.016	TUBB1
RHO GTPases activate IQGAPs	1	346.1×	0.016	TUBB1
Sealing of the nuclear envelope (NE) by ESCRT-III	1	346.1×	0.016	TUBB1
HCMV Infection	1	326.3×	0.016	TUBB1
Chaperonin-mediated protein folding	1	300.5×	0.016	TUBB1
Gap junction assembly	1	292.8×	0.016	TUBB1
Nuclear Envelope (NE) Reassembly	1	292.8×	0.016	TUBB1
Selective autophagy	1	278.5×	0.016	TUBB1
Protein folding	1	259.6×	0.016	TUBB1
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.016	TUBB1
Cargo trafficking to the periciliary membrane	1	248.3×	0.016	TUBB1
Aggrephagy	1	248.3×	0.016	TUBB1
Carboxyterminal post-translational modifications of tubulin	1	237.9×	0.016	TUBB1
Recycling pathway of L1	1	223.9×	0.016	TUBB1
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	TUBB1
Post NMDA receptor activation events	1	203.9×	0.016	TUBB1
Intraflagellar transport	1	200.3×	0.016	TUBB1
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.016	TUBB1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	193.6×	0.016	TUBB1
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.016	TUBB1
Signaling by Hedgehog	1	184.2×	0.016	TUBB1
Hedgehog ‘off’ state	1	178.4×	0.016	TUBB1

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
thyroid hormone transport	1	1685.2×	0.004	TUBB1
microtubule polymerization	1	887.0×	0.004	TUBB1
platelet formation	1	702.2×	0.004	TUBB1
thyroid gland development	1	543.6×	0.004	TUBB1
spindle assembly	1	443.5×	0.004	TUBB1
platelet aggregation	1	337.0×	0.004	TUBB1
mitotic cell cycle	1	133.8×	0.008	TUBB1
microtubule cytoskeleton organization	1	121.2×	0.008	TUBB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
TUBB1	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB1	22	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB1
VINBLASTINE	4	TUBB1
LEVOFLOXACIN ANHYDROUS	4	TUBB1
DOCETAXEL	4	TUBB1
NOSCAPINE	4	TUBB1
VINBLASTINE SULFATE	4	TUBB1
PACLITAXEL	4	TUBB1
LEVOFLOXACIN	4	TUBB1
VINORELBINE	4	TUBB1
TIRBANIBULIN	4	TUBB1
PODOFILOX	4	TUBB1
VINCRISTINE	4	TUBB1
DOCETAXEL ANHYDROUS	4	TUBB1
PATUPILONE	3	TUBB1
TALTOBULIN	2	TUBB1
ABT-751	2	TUBB1
MAYTANSINE	2	TUBB1
DOLASTATIN-10	2	TUBB1
INDIBULIN	2	TUBB1
PARBENDAZOLE	2	TUBB1
NOCODAZOLE	2	TUBB1
COMBRETASTATIN	1	TUBB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB1	1,765	Binding:1723, Functional:36, ADMET:6

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBB1	1,765

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

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	TUBB1
VINBLASTINE	4	TUBB1
LEVOFLOXACIN ANHYDROUS	4	TUBB1
DOCETAXEL	4	TUBB1
NOSCAPINE	4	TUBB1
VINBLASTINE SULFATE	4	TUBB1
PACLITAXEL	4	TUBB1
LEVOFLOXACIN	4	TUBB1
VINORELBINE	4	TUBB1
TIRBANIBULIN	4	TUBB1
PODOFILOX	4	TUBB1
VINCRISTINE	4	TUBB1
DOCETAXEL ANHYDROUS	4	TUBB1
PATUPILONE	3	TUBB1
TALTOBULIN	2	TUBB1
ABT-751	2	TUBB1
MAYTANSINE	2	TUBB1
DOLASTATIN-10	2	TUBB1
INDIBULIN	2	TUBB1
PARBENDAZOLE	2	TUBB1
NOCODAZOLE	2	TUBB1
COMBRETASTATIN	1	TUBB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB1
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.