Thrombomodulin-related bleeding disorder

Summary

Thrombomodulin-related bleeding disorder (MONDO:0013775) is a disease caused by THBD (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: THBD (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 205

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombomodulin-related bleeding disorder
Mondo ID	MONDO:0013775
MeSH	C566057
OMIM	614486
Orphanet	436169
DOID	DOID:0111908
UMLS	C3280976
MedGen	482606
GARD	0017726
Is cancer (heuristic)	no

Also known as: THBD-related bleeding disorder · THBD-related coagulopathy · THPH12 · thrombomodulin-related coagulopathy · thrombophilia 12 due to thrombomodulin defect · thrombophilia due to thrombomodulin defect

Data availability: 205 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › thrombomodulin-related bleeding disorder

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, thrombophilia due to activated protein C resistance, hypoplasminogenemia, congenital high-molecular-weight kininogen deficiency, congenital factor XII deficiency, alpha-2-plasmin inhibitor deficiency, Tatsumi factor deficiency, East Texas bleeding disorder, inherited prekallikrein deficiency, congenital plasminogen activator inhibitor type 1 deficiency, congenital vitamin K-dependent coagulation factors deficiency, hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, congenital fibrinogen deficiency, combined deficiency of factor V and factor VIII, hemophilia, factor V deficiency, acquired coagulation factor deficiency, von Willebrand disease (hereditary or acquired), factor V short isoforms-related bleeding disorder, factor V amsterdam bleeding disorder, factor V atlanta bleeding disorder, combined deficiency of factor VII and factor X, plasminogen deficiency, type II, dysplasminogenemia

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

205 retrieved; paginated sample, class counts are floors:

161 uncertain significance, 16 conflicting classifications of pathogenicity, 8 likely benign, 7 benign/likely benign, 6 benign, 6 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12715	NM_000361.3(THBD):c.142G>A (p.Ala48Thr)	THBD	Pathogenic	no assertion criteria provided
3587112	NM_000361.3(THBD):c.1360del (p.Val454fs)	THBD	Likely pathogenic	criteria provided, single submitter
3587124	NM_000361.3(THBD):c.920C>A (p.Ser307Ter)	THBD	Likely pathogenic	criteria provided, single submitter
3587142	NM_000361.3(THBD):c.127del (p.Ala43fs)	THBD	Likely pathogenic	criteria provided, single submitter
3893285	NM_000361.3(THBD):c.1440_1441del (p.Cys480_Asp481delinsTer)	THBD	Likely pathogenic	criteria provided, single submitter
627170	NM_000361.3(THBD):c.1487del (p.Pro496fs)	THBD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
627252	NM_000361.3(THBD):c.1611C>A (p.Cys537Ter)	THBD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012154	NM_000361.3(THBD):c.77G>C (p.Gly26Ala)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062110	NM_000361.3(THBD):c.277C>A (p.Pro93Thr)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12718	NM_000361.3(THBD):c.127G>A (p.Ala43Thr)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12720	NM_000361.3(THBD):c.1483C>T (p.Pro495Ser)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1369949	NM_000361.3(THBD):c.707C>G (p.Ala236Gly)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434632	NM_000361.3(THBD):c.1406A>G (p.Asp469Gly)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1525345	NM_000361.3(THBD):c.483G>T (p.Lys161Asn)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1553770	NM_000361.3(THBD):c.1361T>C (p.Val454Ala)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1712464	NM_000361.3(THBD):c.1057C>A (p.Pro353Thr)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2572117	NM_000361.3(THBD):c.844G>C (p.Ala282Pro)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2976020	NM_000361.3(THBD):c.623C>G (p.Pro208Arg)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3587134	NM_000361.3(THBD):c.459G>A (p.Trp153Ter)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626184	NM_000361.3(THBD):c.683C>T (p.Pro228Leu)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627282	NM_000361.3(THBD):c.245del (p.Gly82fs)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
734869	NM_000361.3(THBD):c.1504G>C (p.Gly502Arg)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897138	NM_000361.3(THBD):c.302G>C (p.Arg101Pro)	THBD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017467	NM_000361.3(THBD):c.1062C>G (p.Asn354Lys)	THBD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022187	NM_000361.3(THBD):c.302G>T (p.Arg101Leu)	THBD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029800	NM_000361.3(THBD):c.994G>T (p.Glu332Ter)	THBD	Uncertain significance	criteria provided, single submitter
1045160	NM_000361.3(THBD):c.119C>T (p.Pro40Leu)	THBD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1163156	NM_000361.3(THBD):c.448G>A (p.Glu150Lys)	THBD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1163744	NM_000361.3(THBD):c.1678G>C (p.Glu560Gln)	THBD	Uncertain significance	criteria provided, multiple submitters, no conflicts
12716	NM_000361.3(THBD):c.1688dup (p.Gln564fs)	THBD	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
THBD	Strong	Autosomal dominant	thrombomodulin-related bleeding disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THBD	Orphanet:436169	Thrombomodulin-related bleeding disorder
THBD	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality

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
THBD	HGNC:11784	ENSG00000178726	P07204	Thrombomodulin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THBD	Thrombomodulin	Endothelial cell receptor that plays a critical role in regulating several physiological processes including hemostasis, coagulation, fibrinolysis, inflammation, and angiogenesis.

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)
THBD	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, C-type_lectin-like

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
gingiva	1
gingival epithelium	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THBD	259	ubiquitous	marker	gingival epithelium, gingiva, vena cava

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
THBD	2,746

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
THBD	P07204	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Regulation of clotting cascade	1	233.1×	0.009	THBD
Cell surface interactions at the vascular wall	1	95.2×	0.011	THBD

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
blood coagulation, common pathway	1	8426.0×	0.001	THBD
negative regulation of platelet activation	1	1872.4×	0.002	THBD
negative regulation of fibrinolysis	1	1404.3×	0.002	THBD
negative regulation of blood coagulation	1	1203.7×	0.002	THBD
response to X-ray	1	887.0×	0.002	THBD
zymogen activation	1	674.1×	0.003	THBD
response to cAMP	1	510.7×	0.003	THBD
female pregnancy	1	210.7×	0.007	THBD
blood coagulation	1	173.7×	0.007	THBD
response to lipopolysaccharide	1	124.8×	0.009	THBD
proteolysis	1	34.2×	0.029	THBD

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THBD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	THBD

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)
THBD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.