Bleeding disorder, platelet-type, 25

Summary

Bleeding disorder, platelet-type, 25 (MONDO:0957580) is a disease caused by TPM4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TPM4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bleeding disorder, platelet-type, 25
Mondo ID	MONDO:0957580
OMIM	620486
UMLS	C5882683
MedGen	1846290
GARD	0026869
Is cancer (heuristic)	no

Data availability: 4 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › hemorrhagic disease › inherited bleeding disorder, platelet-type › bleeding disorder, platelet-type, 25

Related subtypes (27): gray platelet syndrome, primary release disorder of platelets, platelet-type von Willebrand disease, platelet-type bleeding disorder 16, platelet-type bleeding disorder 17, Ehlers-Danlos syndrome, fibronectinemic type, Bernard-Soulier syndrome, Scott syndrome, congenital thrombotic thrombocytopenic purpura, Quebec platelet disorder, platelet-type bleeding disorder 12, platelet-type bleeding disorder 10, platelet-type bleeding disorder 8, platelet-type bleeding disorder 14, platelet-type bleeding disorder 9, platelet-type bleeding disorder 11, platelet-type bleeding disorder 15, platelet-type bleeding disorder 18, platelet-type bleeding disorder 19, platelet-type bleeding disorder 20, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder, bleeding disorder, platelet-type, 24, bleeding disorder, platelet-type, 22, bleeding disorder, platelet-type, 21, Glanzmann thrombasthenia, bleeding diathesis due to thromboxane synthesis deficiency

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

4 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2577543	NM_003290.3(TPM4):c.436C>T (p.Arg146Cys)	TPM4	Pathogenic	no assertion criteria provided
2577544	NM_003290.3(TPM4):c.322C>T (p.Gln108Ter)	TPM4	Pathogenic	criteria provided, single submitter
2577545	NM_003290.3(TPM4):c.205C>T (p.Arg69Ter)	TPM4	Pathogenic	no assertion criteria provided
4526536	NM_003290.3(TPM4):c.385-2A>G	TPM4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
TPM4	Strong	Autosomal dominant	bleeding disorder, platelet-type, 25	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPM4	Orphanet:140957	Autosomal dominant macrothrombocytopenia
TPM4	Orphanet:178342	Inflammatory myofibroblastic tumor

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
TPM4	HGNC:12013	ENSG00000167460	P67936	Tropomyosin alpha-4 chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPM4	Tropomyosin alpha-4 chain	Binds to actin filaments in muscle and non-muscle cells.

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)
TPM4	Other/Unknown	no		Tropomyosin, XRCC4-like_C

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
right coronary artery	1
stromal cell of endometrium	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPM4	281	ubiquitous	marker	tendon of biceps brachii, stromal cell of endometrium, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM4	557

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPM4	P67936	93.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Striated Muscle Contraction	1	308.6×	0.005	TPM4
RHOV GTPase cycle	1	285.5×	0.005	TPM4
Smooth Muscle Contraction	1	265.6×	0.005	TPM4
Signaling by ALK fusions and activated point mutants	1	150.3×	0.007	TPM4

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
platelet formation	1	702.2×	0.006	TPM4
muscle contraction	1	208.1×	0.008	TPM4
osteoblast differentiation	1	121.2×	0.008	TPM4
actin filament organization	1	118.7×	0.008	TPM4

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
TPM4	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
TPM4	4	Binding:4

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	TPM4

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)
TPM4	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.