hereditary thrombophilia due to congenital protein C deficiency

Summary

hereditary thrombophilia due to congenital protein C deficiency (MONDO:0019145) is a disease caused by PROC (GenCC Definitive), with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include protein c concentrate (human).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PROC (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 4
• Phenotypes (HPO): 10
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.16	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000963	Thin skin	Frequent (30-79%)
HP:0000979	Purpura	Frequent (30-79%)
HP:0004936	Venous thrombosis	Frequent (30-79%)
HP:0008065	Aplasia/Hypoplasia of the skin	Frequent (30-79%)
HP:0001000	Abnormality of skin pigmentation	Occasional (5-29%)
HP:0001038	Warfarin-induced skin necrosis	Occasional (5-29%)
HP:0002204	Pulmonary embolism	Occasional (5-29%)
HP:0005293	Venous insufficiency	Occasional (5-29%)
HP:0100659	Abnormality of the cerebral vasculature	Occasional (5-29%)
HP:0100758	Gangrene	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary thrombophilia due to congenital protein C deficiency
Mondo ID	MONDO:0019145
MeSH	C535424, D020151
Orphanet	745
DOID	DOID:3756
ICD-11	2021932081
NCIT	C99025
SNOMED CT	76407009
UMLS	C0598221
MedGen	671121
GARD	0016544
NORD	1899
Is cancer (heuristic)	no

Also known as: hereditary thrombophilia due to congenital protein C deficiency · Protein C Deficiency · Protein C deficiency · protein C deficiency · Protein C deficiency disease · severe hereditary thrombophilia due to congenital protein C deficiency

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › thrombophilia › inherited thrombophilia › hereditary thrombophilia due to congenital protein C deficiency

Related subtypes (11): factor 5 excess with spontaneous thrombosis, thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance, thrombophilia, X-linked, due to factor 9 defect, thrombophilia, familial, due to decreased release of tissue plasminogen activator, heparin cofactor 2 deficiency, hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency, hereditary antithrombin deficiency, thrombomodulin-related bleeding disorder, hereditary thrombophilia due to congenital protein S deficiency, thrombophilia, X-linked, due to factor 8 defect

Subtypes (2): thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive

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/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
188230	NM_000312.4(PROC):c.169C>T (p.Arg57Trp)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
661	NM_000312.4(PROC):c.629C>T (p.Pro210Leu)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
662	NM_000312.4(PROC):c.925G>A (p.Ala309Thr)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2775426	NM_000312.4(PROC):c.1265G>A (p.Trp422Ter)	PROC	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
PROC	Definitive	Autosomal dominant	thrombophilia due to protein C deficiency, autosomal dominant	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PROC	Orphanet:745	Severe hereditary thrombophilia due to congenital protein C deficiency

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
PROC	HGNC:9451	ENSG00000115718	P04070	Vitamin K-dependent protein C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PROC	Vitamin K-dependent protein C	Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PROC	Protease	yes	3.4.21.69	EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF

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
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
PROC	165	broad	marker	right lobe of liver, liver, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PROC	1,449

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PROC	P04070	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Defective cleavage of FV variant at a.a.534	1	3806.7×	0.001	PROC
Defective cleavage of FV variant at R334	1	3806.7×	0.001	PROC
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	1268.9×	0.002	PROC
Gamma-carboxylation of protein precursors	1	1142.0×	0.002	PROC
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	1142.0×	0.002	PROC
Fibrin formation	1	878.5×	0.002	PROC
Amplification and propagation of coagulation cascade	1	634.4×	0.002	PROC
Regulation of clotting cascade	1	233.1×	0.006	PROC
Post-translational protein phosphorylation	1	100.2×	0.012	PROC
Cell surface interactions at the vascular wall	1	95.2×	0.012	PROC
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	PROC

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
negative regulation of coagulation	1	4213.0×	0.001	PROC
positive regulation of establishment of endothelial barrier	1	2808.7×	0.001	PROC
negative regulation of blood coagulation	1	1203.7×	0.002	PROC
blood coagulation	1	173.7×	0.010	PROC
negative regulation of inflammatory response	1	137.0×	0.010	PROC
negative regulation of apoptotic process	1	34.8×	0.029	PROC
proteolysis	1	34.2×	0.029	PROC

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Protein C Concentrate (Human)	Approved (phase 4)

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
PROC	MELAGATRAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PROC	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MELAGATRAN	4	PROC
DABIGATRAN	3	PROC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PROC	117	Binding:117

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PROC	3.4.21.69	activated protein C (thrombin-activated peptidase)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PROC	117

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

2 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)
MELAGATRAN	4	PROC
DABIGATRAN	3	PROC

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PROC
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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2/PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00157118	PHASE2/PHASE3	COMPLETED	Efficacy and Safety Study of Protein C Concentrate in Subjects With Severe Congenital Protein C Deficiency
NCT04984889	PHASE1/PHASE2	COMPLETED	A Study of TAK-662 for Japanese Patients With Congenital Protein C Deficiency
NCT06590974	Not specified	RECRUITING	A Study of Freeze-dried Human Protein C Concentrate (TAK-662) in Participants With Congenital Protein C Deficiency
NCT00161720	Not specified	COMPLETED	Retrospective Study to Capture Dosing and Treatment Outcome Data in Participants With Severe Congenital Protein C Deficiency Who Were Treated With Protein C Concentrate Under an Emergency Use IND
NCT01127529	Not specified	COMPLETED	Ceprotin Treatment Registry
NCT04180657	Not specified	UNKNOWN	Ghrelin Levels in Patients With Protein C Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PROTEIN C CONCENTRATE (HUMAN)	4	1