thrombophilia due to protein C deficiency, autosomal recessive

Summary

thrombophilia due to protein C deficiency, autosomal recessive (MONDO:0012860) is a disease caused by PROC (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PROC (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 60

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombophilia due to protein C deficiency, autosomal recessive
Mondo ID	MONDO:0012860
MeSH	C567353
OMIM	612304
DOID	DOID:0111904
UMLS	C2676759
MedGen	394120
GARD	0013041
Is cancer (heuristic)	no

Also known as: autosomal recessive hereditary thrombophilia due to protein C deficiency · autosomal recessive protein C deficiency · hereditary thrombophilia due to congenital protein C deficiency · hereditary thrombophilia due to PC deficiency · THPH4 · thrombophilia 3 due to protein C deficiency, autosomal recessive · thrombophilia due to protein C deficiency, autosomal recessive

Data availability: 60 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 › thrombophilia › inherited thrombophilia › hereditary thrombophilia due to congenital protein C deficiency › thrombophilia due to protein C deficiency, autosomal recessive

Related subtypes (1): thrombophilia due to protein C deficiency, 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

60 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 13 pathogenic/likely pathogenic, 11 conflicting classifications of pathogenicity, 8 pathogenic, 4 benign, 3 likely benign, 2 benign/likely benign, 1 likely pathogenic

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
1074000	NM_000312.4(PROC):c.520C>T (p.Gln174Ter)	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
1427775	NM_000312.4(PROC):c.1218G>A (p.Met406Ile)	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
4292624	NM_000312.4(PROC):c.715_724del (p.Gly239fs)	PROC	Pathogenic	criteria provided, single submitter
536970	NM_000312.4(PROC):c.811C>T (p.Arg271Trp)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
658	PROC, ARG12TRP	PROC	Pathogenic	no assertion criteria provided
659	NM_000312.4(PROC):c.631C>T (p.Arg211Trp)	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
663	NM_000312.4(PROC):c.1027G>A (p.Gly343Ser)	PROC	Pathogenic	no assertion criteria provided
663591	NM_000312.4(PROC):c.889G>C (p.Asp297His)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
664	NM_000312.4(PROC):c.185A>C (p.Glu62Ala)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
665	NM_000312.4(PROC):c.226G>A (p.Val76Met)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
667	NM_000312.4(PROC):c.866C>T (p.Pro289Leu)	PROC	Pathogenic	no assertion criteria provided
668	NM_000312.4(PROC):c.658C>T (p.Arg220Trp)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
669	NM_000312.4(PROC):c.659G>A (p.Arg220Gln)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
676	NM_000312.4(PROC):c.1335C>G (p.Ile445Met)	PROC	Pathogenic	no assertion criteria provided
839161	NM_000312.4(PROC):c.595C>T (p.Arg199Ter)	PROC	Pathogenic	criteria provided, multiple submitters, no conflicts
932369	NM_000312.4(PROC):c.124C>T (p.Arg42Cys)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
660	NM_000312.4(PROC):c.902C>T (p.Ala301Val)	PROC	Likely pathogenic	criteria provided, single submitter
1067044	NM_000312.4(PROC):c.1106C>T (p.Pro369Leu)	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1455313	NM_000312.4(PROC):c.303C>A (p.Cys101Ter)	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676213	NM_000312.4(PROC):c.703A>C (p.Lys235Gln)	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1947958	NM_000312.4(PROC):c.1321T>C (p.Tyr441His)	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331101	NM_000312.4(PROC):c.-21-5C>T	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331113	NM_000312.4(PROC):c.1318C>T (p.Arg440Cys)	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469121	NM_000312.4(PROC):c.30C>T (p.Phe10=)	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627215	NM_000312.4(PROC):c.1163C>T (p.Ala388Val)	PROC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PROC	HGNC:9451	ENSG00000115718	P04070	Vitamin K-dependent protein C	gencc,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.
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: 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	18.3×	0.108
Enzyme (other)	1	6.0×	0.160

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
PC	Enzyme (other)	yes	6.4.1.1	Biotin_lipoyl, PYR_CT, Biotin_BS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
adult mammalian kidney	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
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
PC	2,984
PROC	1,449

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PROC	P04070	12
PC	P11498	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 2 evidence-associated genes (2 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 2 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	1903.3×	0.004	PROC
Defective cleavage of FV variant at R334	1	1903.3×	0.004	PROC
Defective HLCS causes multiple carboxylase deficiency	1	815.7×	0.004	PC
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	634.4×	0.004	PROC
Gamma-carboxylation of protein precursors	1	571.0×	0.004	PROC
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	571.0×	0.004	PROC
Biotin transport and metabolism	1	519.1×	0.004	PC
Fibrin formation	1	439.2×	0.004	PROC
Amplification and propagation of coagulation cascade	1	317.2×	0.005	PROC
Gluconeogenesis	1	219.6×	0.007	PC
Pyruvate metabolism	1	203.9×	0.007	PC
Regulation of clotting cascade	1	116.5×	0.011	PROC
Post-translational protein phosphorylation	1	50.1×	0.022	PROC
Cell surface interactions at the vascular wall	1	47.6×	0.022	PROC
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.023	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 2 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	4213.0×	0.004	PC
negative regulation of coagulation	1	2106.5×	0.004	PROC
positive regulation of establishment of endothelial barrier	1	1404.3×	0.004	PROC
NAD+ metabolic process	1	936.2×	0.004	PC
NADP+ metabolic process	1	766.0×	0.004	PC
host-mediated activation of viral process	1	702.2×	0.004	PC
negative regulation of blood coagulation	1	601.9×	0.004	PROC
viral release from host cell	1	468.1×	0.004	PC
gluconeogenesis	1	162.0×	0.010	PC
blood coagulation	1	86.9×	0.017	PROC
negative regulation of inflammatory response	1	68.5×	0.020	PROC
lipid metabolic process	1	45.8×	0.027	PC
negative regulation of gene expression	1	34.5×	0.033	PC
negative regulation of apoptotic process	1	17.4×	0.058	PROC
proteolysis	1	17.1×	0.058	PROC

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
PC	0	0

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): 2.

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

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

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: 2; 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	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.