GeneBe

PROC

protein-coding

protein C, inactivator of coagulation factors Va and VIIIa, the group of Gla domain containing|Receptor ligands

Gene summary

This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

MANE transcript

NM_000312.4

Inheritance

AR, AD, SD

ClinVar variants

P:133U:168B:92

Top phenotype

Thrombophilia, hereditary, due to protein C deficiency

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr2:127,418,427-127,429,242

External References & Databases

Ensembl (ENSG00000115718)NCBI Gene (5624)OMIM (612283)HGNC:9451GenCCUniProt (P04070)AlphaFoldClinVar (PROC)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~10.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thrombophilia due to protein C deficiency, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012860

Submitter: Genomics England PanelApp

thrombophilia due to protein C deficiency, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008316

Submitter: Ambry Genetics

thrombophilia due to protein C deficiency, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012860

Submitter: PanelApp Australia

thrombophilia due to protein C deficiency, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008316

Submitter: PanelApp Australia

hereditary thrombophilia due to congenital protein C deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0019145

Submitter: ClinGen

PROC was first reported in relation to semidominant hereditary thrombophilia due to congenital protein C deficiency in 1987 (Romeo G, et al., 1987, PMID: 2437584). Over 400 unique variants (primarily missense, but also nonsense, splicing, frameshifts, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 20 probands in 5 publications (PMIDs: 2437584, 25393254, 11380450, 25618265, and 21621249). Variants in this gene segregated with disease in 14 additional family members. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease relationship is supported by its biochemical function in factor V and VIII inactivation (PMID: 6791548), its interaction with protein S (PMID: 28514442) and both deficient and null mouse models which recapitulate phenotypes observed in humans (PMID: 15902301, PMID: 9788960). In summary, PROC is definitively associated with semidominant hereditary thrombophilia due to congenital protein C deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

thrombophilia due to protein C deficiency, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008316

Submitter: Genomics England PanelApp

hereditary thrombophilia due to congenital protein C deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019145

Submitter: Orphanet

thrombophilia due to protein C deficiency, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008316

Submitter: Labcorp Genetics (formerly Invitae)

thrombophilia due to protein C deficiency, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012860

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Thrombophilia, hereditary, due to protein C deficiencyAD/AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals can demonstrate manifestations such as severe thrombophilia and high risk for a variety of cardiovascular complications, and prophylactic measures and rapid treatment of sequelae may reduce morbidity and mortality; Liver and renal transplantation have been described

Comments: The risks of hematologic complications may be affected by variants in other genes (eg, FVL)

Refs: 6895379; 6139528; 6148564; 6547008; 6437521; 3840918; 2958610; 2437584; 3337902; 2521802; 2547423; 1944440; 8093743; 8322701; 8446940; 8049422; 7795227; 7562967; 8750805; 10942114; 11148525; 19373522; 20187890; 20727573; 22168450; 22531345Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PROC variants in ClinVar

14 Conditions Cataloged
Thrombophilia due to protein C deficiency, autosomal dominantTotal: 359
not providedTotal: 116
Thrombophilia due to protein C deficiency, autosomal recessiveTotal: 63
PROC-related disorderTotal: 52
not specifiedTotal: 34
Reduced protein C activityTotal: 32
Inborn genetic diseasesTotal: 16
Deep venous thrombosisTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000312.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
5
clinvar
87
clinvar
 92
missense
12
clinvar
79
clinvar
160
clinvar
5
clinvar
 256
nonsense
11
clinvar
8
clinvar
2
clinvar
 21
start loss
0
frameshift
7
clinvar
7
clinvar
1
clinvar
 15
splice donor/acceptor (+/-2bp)
3
clinvar
6
clinvar
 9
Total33100168920393

Highest pathogenic variant AF is 0.00023172186

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 210 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000312.4RefSeqNP_000303.18MANE Select
ENST00000234071.8EnsemblENSP00000234071.48MANE Select
NM_001375602.1RefSeqNP_001362531.19Standard
NM_001375603.1RefSeqNP_001362532.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Complement and coagulation cascades - Homo sapiens (human)
  • Warfarin Pathway, Pharmacodynamics
  • Dengue-2 Interactions with Complement and Coagulation Cascades
  • Complement and Coagulation Cascades
  • wnt signaling pathway

Biological Process

  • proteolysis
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • blood coagulation
  • negative regulation of blood coagulation
  • negative regulation of apoptotic process

Molecular Function

  • serine-type endopeptidase activity
  • calcium ion binding
  • protein binding

Cellular Component

  • extracellular region
  • extracellular space
  • endoplasmic reticulum
  • endoplasmic reticulum lumen
  • Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000234071
Coding exons
8
Length
10820
Individuals with no LoFs
125728
Homozygous LoFs
0
Heterozygous LoFs
18
Defined
125746
p
0.0000716
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8832352760.8500.00001833044
Missense (PolyPhen)73102.860.709671133
Synonymous0.7221021120.9130.00000756863
Loss of Function2.031121.10.5220.00000110220

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish00.0absent
European (Non-Finnish)0.0000270.000026rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: 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 (PubMed:25618265). Exerts a protective effect on the endothelial cell barrier function (PubMed:25651845). {ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:25651845}.;
Disease
DISEASE: Thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency. {ECO:0000269|PubMed:1301959, ECO:0000269|PubMed:1347706, ECO:0000269|PubMed:1511989, ECO:0000269|PubMed:1868249, ECO:0000269|PubMed:2437584, ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:25748729, ECO:0000269|PubMed:2602169, ECO:0000269|PubMed:7792728, ECO:0000269|PubMed:7865674, ECO:0000269|PubMed:8292730, ECO:0000269|PubMed:8398832, ECO:0000269|PubMed:8499568, ECO:0000269|PubMed:8560401, ECO:0000269|PubMed:8829639, ECO:0000269|PubMed:9798967}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare. {ECO:0000269|PubMed:1511988, ECO:0000269|PubMed:1593215, ECO:0000269|PubMed:1611081, ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:7841323, ECO:0000269|PubMed:7841324, ECO:0000269|PubMed:7878626}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.657

Intolerance Scores

LoFtool
0.0970
RVIS EVS
-0.6
RVIS percentile EVS
17.91

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.707

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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