thrombophilia due to protein C deficiency, autosomal dominant

Summary

thrombophilia due to protein C deficiency, autosomal dominant (MONDO:0008316) is a disease caused by PROC (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: PROC (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 378

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombophilia due to protein C deficiency, autosomal dominant
Mondo ID	MONDO:0008316
OMIM	176860
DOID	DOID:0111909
UMLS	C2674321
MedGen	436138
GARD	0018574
Is cancer (heuristic)	no

Also known as: THPH3 · thrombophilia 3 due to protein C deficiency, autosomal dominant · thrombophilia due to protein C deficiency, autosomal dominant

Data availability: 378 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 › thrombophilia due to protein C deficiency, autosomal dominant

Related subtypes (1): 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

378 retrieved; paginated sample, class counts are floors:

141 uncertain significance, 101 likely benign, 39 conflicting classifications of pathogenicity, 34 pathogenic, 22 pathogenic/likely pathogenic, 21 likely pathogenic, 11 benign, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070920	NM_001040716.2(PC):c.1663C>T (p.Arg555Ter)	PC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048661	NM_000312.4(PROC):c.632G>A (p.Arg211Gln)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048662	NM_000312.4(PROC):c.400+2T>C	PROC	Pathogenic	criteria provided, single submitter
1048663	NM_000312.4(PROC):c.479G>C (p.Cys160Ser)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068737	NM_000312.4(PROC):c.561G>A (p.Trp187Ter)	PROC	Pathogenic	criteria provided, single submitter
1073999	NM_000312.4(PROC):c.400G>T (p.Glu134Ter)	PROC	Pathogenic	criteria provided, single submitter
1074000	NM_000312.4(PROC):c.520C>T (p.Gln174Ter)	PROC	Pathogenic	criteria provided, multiple submitters, no conflicts
1389677	NM_000312.4(PROC):c.445dup (p.His149fs)	PROC	Pathogenic	criteria provided, multiple submitters, no conflicts
1394296	NM_000312.4(PROC):c.541T>G (p.Phe181Val)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1420279	NM_000312.4(PROC):c.675G>A (p.Trp225Ter)	PROC	Pathogenic	criteria provided, single submitter
1427775	NM_000312.4(PROC):c.1218G>A (p.Met406Ile)	PROC	Pathogenic	criteria provided, multiple submitters, no conflicts
161334	NM_000312.4(PROC):c.1201G>A (p.Asp401Asn)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676815	NM_000312.4(PROC):c.151C>T (p.Arg51Cys)	PROC	Pathogenic	criteria provided, multiple submitters, no conflicts
188230	NM_000312.4(PROC):c.169C>T (p.Arg57Trp)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1976706	NM_000312.4(PROC):c.698dup (p.Lys234fs)	PROC	Pathogenic	criteria provided, single submitter
1992373	NM_000312.4(PROC):c.94C>T (p.Arg32Cys)	PROC	Pathogenic	criteria provided, multiple submitters, no conflicts
2203144	NM_000312.4(PROC):c.560G>A (p.Trp187Ter)	PROC	Pathogenic	criteria provided, single submitter
2203147	NM_000312.4(PROC):c.907_908del (p.Leu303fs)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2700349	NM_000312.4(PROC):c.6G>A (p.Trp2Ter)	PROC	Pathogenic	criteria provided, single submitter
2734266	NM_000312.4(PROC):c.400+5G>T	PROC	Pathogenic	criteria provided, single submitter
3247344	NC_000002.11:g.(?128175983)(128184818_?)del	PROC	Pathogenic	criteria provided, single submitter
3573001	NM_000312.4(PROC):c.360C>A (p.Cys120Ter)	PROC	Pathogenic	criteria provided, single submitter
3716585	NM_000312.4(PROC):c.400+2T>A	PROC	Pathogenic	criteria provided, single submitter
3720362	NM_000312.4(PROC):c.400+5G>A	PROC	Pathogenic	criteria provided, single submitter
407370	NM_000312.4(PROC):c.1212dup (p.Pro405fs)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4540671	NM_000312.4(PROC):c.604G>T (p.Glu202Ter)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4698752	NM_000312.4(PROC):c.1115dup (p.Cys373fs)	PROC	Pathogenic	criteria provided, single submitter
4734045	NM_000312.4(PROC):c.714C>A (p.Cys238Ter)	PROC	Pathogenic	criteria provided, single submitter
4735017	NM_000312.4(PROC):c.318C>A (p.Cys106Ter)	PROC	Pathogenic	criteria provided, single submitter
522437	NM_000312.4(PROC):c.340G>T (p.Gly114Cys)	PROC	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
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
PC	Orphanet:353308	Pyruvate carboxylase deficiency, infantile type
PC	Orphanet:353314	Pyruvate carboxylase deficiency, severe neonatal type
PC	Orphanet:353320	Pyruvate carboxylase deficiency, benign type

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PROC	HGNC:9451	ENSG00000115718	P04070	Vitamin K-dependent protein C	gencc,clinvar
WDR33	HGNC:25651	ENSG00000136709	Q9C0J8	pre-mRNA 3’ end processing protein WDR33	clinvar
PC	HGNC:8636	ENSG00000173599	P11498	Pyruvate carboxylase, mitochondrial	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.
WDR33	pre-mRNA 3’ end processing protein WDR33	Essential for both cleavage and polyadenylation of pre-mRNA 3’ ends.
PC	Pyruvate carboxylase, mitochondrial	Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	12.2×	0.230
Scaffold/PPI	1	5.8×	0.230
Enzyme (other)	1	4.0×	0.230

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
WDR33	Scaffold/PPI	no		WD40_rpt, Collagen, WD40/YVTN_repeat-like_dom_sf
PC	Enzyme (other)	yes	6.4.1.1	Biotin_lipoyl, PYR_CT, Biotin_BS

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
adult mammalian kidney	1
gingiva	1
gingival epithelium	1
vena cava	1
right frontal lobe	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
WDR33	269	ubiquitous	marker	gingival epithelium, vena cava, gingiva
PC	204	ubiquitous	marker	right lobe of liver, liver, right frontal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDR33	3,523
PC	2,984
PROC	1,449

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDR33	Q9C0J8	13
PROC	P04070	12
PC	P11498	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 3 evidence-associated genes (3 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 3 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	1268.9×	0.008	PROC
Defective cleavage of FV variant at R334	1	1268.9×	0.008	PROC
Defective HLCS causes multiple carboxylase deficiency	1	543.8×	0.009	PC
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	423.0×	0.009	PROC
Gamma-carboxylation of protein precursors	1	380.7×	0.009	PROC
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	380.7×	0.009	PROC
Biotin transport and metabolism	1	346.1×	0.009	PC
Fibrin formation	1	292.8×	0.009	PROC
Amplification and propagation of coagulation cascade	1	211.5×	0.011	PROC
Processing of Intronless Pre-mRNAs	1	190.3×	0.011	WDR33
Gluconeogenesis	1	146.4×	0.013	PC
Pyruvate metabolism	1	135.9×	0.013	PC
Transport of Mature mRNA Derived from an Intronless Transcript	1	90.6×	0.018	WDR33
Regulation of clotting cascade	1	77.7×	0.019	PROC
RNA Polymerase II Transcription Termination	1	73.2×	0.019	WDR33
mRNA 3’-end processing	1	65.6×	0.020	WDR33
Post-translational protein phosphorylation	1	33.4×	0.036	PROC
Cell surface interactions at the vascular wall	1	31.7×	0.036	PROC
mRNA Polyadenylation	1	29.3×	0.036	WDR33
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.036	PROC
Dengue Virus-Host Interactions	1	15.2×	0.064	WDR33

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
viral RNA genome packaging	1	2808.7×	0.005	PC
negative regulation of coagulation	1	1404.3×	0.005	PROC
positive regulation of establishment of endothelial barrier	1	936.2×	0.005	PROC
NAD+ metabolic process	1	624.1×	0.005	PC
DNA damage tolerance	1	561.7×	0.005	WDR33
NADP+ metabolic process	1	510.7×	0.005	PC
host-mediated activation of viral process	1	468.1×	0.005	PC
negative regulation of blood coagulation	1	401.2×	0.006	PROC
viral release from host cell	1	312.1×	0.006	PC
mRNA 3’-end processing	1	187.2×	0.010	WDR33
gluconeogenesis	1	108.0×	0.015	PC
blood coagulation	1	57.9×	0.026	PROC
negative regulation of inflammatory response	1	45.7×	0.030	PROC
lipid metabolic process	1	30.5×	0.042	PC
negative regulation of gene expression	1	23.0×	0.051	PC
spermatogenesis	1	11.7×	0.085	WDR33
negative regulation of apoptotic process	1	11.6×	0.085	PROC
proteolysis	1	11.4×	0.085	PROC

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
WDR33	1	2
PC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MELAGATRAN	4	PROC
DABIGATRAN	3	PROC
MOLIBRESIB	2	WDR33

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PROC	117	Binding:117
PC	10	Binding:10
WDR33	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PROC	3.4.21.69	activated protein C (thrombin-activated peptidase)
PC	6.4.1.1	pyruvate carboxylase

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: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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
MOLIBRESIB	2	WDR33

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	1	WDR33
C	Druggable family + PDB, no drug	1	PC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
PC	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.