PROC

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

Basic information

Region (hg38): 2:127418427-127429242

Links

ENSG00000115718 ∙ NCBI:5624 ∙ OMIM:612283 ∙ HGNC:9451 ∙ Uniprot:P04070 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thrombophilia due to protein C deficiency, autosomal dominant (Strong), mode of inheritance: AD
• thrombophilia due to protein C deficiency, autosomal recessive (Strong), mode of inheritance: AR
• hereditary thrombophilia due to congenital protein C deficiency (Supportive), mode of inheritance: AD
• thrombophilia due to protein C deficiency, autosomal dominant (Strong), mode of inheritance: AD
• thrombophilia due to protein C deficiency, autosomal recessive (Strong), mode of inheritance: AR
• hereditary thrombophilia due to congenital protein C deficiency (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Thrombophilia, hereditary, due to protein C deficiency	AD/AR	Hematologic	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	Hematologic	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; 22531345
The risks of hematologic complications may be affected by variants in other genes (eg, FVL)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PROC gene.

• Thrombophilia due to protein C deficiency, autosomal dominant (22 variants)
• not provided (5 variants)
• Thrombophilia due to protein C deficiency, autosomal recessive (2 variants)
• PROC-related disorder (1 variants)
• Thrombophilia due to protein C deficiency, autosomal recessive;Thrombophilia due to protein C deficiency, autosomal dominant (1 variants)
• Thrombophilia due to protein C deficiency, autosomal dominant;Thrombophilia due to protein C deficiency, autosomal recessive (1 variants)
• Inborn genetic diseases (1 variants)
• Reduced protein C activity (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PROC gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	58	2	64
missense	9	39	111	1		160
nonsense	8	5	1			14
start loss						0
frameshift	4	5	1			10
inframe indel			3			3
splice donor/acceptor (+/-2bp)	2	5				7
splice region	1		5	5	1	12
non coding			11	22	14	47
Total	23	54	131	81	16

Highest pathogenic variant AF is 0.0000328

Variants in PROC

This is a list of pathogenic ClinVar variants found in the PROC region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-127418459-C-T		Thrombophilia due to protein C deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
2-127418460-G-A		Thrombophilia due to protein C deficiency, autosomal dominant	Conflicting classifications of pathogenicity (Nov 06, 2022)
2-127418463-G-A		PROC-related disorder	Likely benign (May 15, 2019)
2-127418464-A-T		not specified • Thrombophilia due to protein C deficiency, autosomal dominant	Benign (Jan 15, 2024)
2-127418481-C-T		Thrombophilia due to protein C deficiency, autosomal dominant • PROC-related disorder	Likely benign (Jan 12, 2018)
2-127418482-G-A		PROC-related disorder	Likely benign (Apr 12, 2019)
2-127419801-C-T			Benign (Nov 12, 2018)
2-127419917-C-T		Thrombophilia due to protein C deficiency, autosomal dominant	Likely benign (Jan 13, 2018)
2-127419948-G-A		Thrombophilia due to protein C deficiency, autosomal dominant	Pathogenic (Dec 02, 2023)
2-127419962-T-C		Thrombophilia due to protein C deficiency, autosomal dominant	Uncertain significance (Oct 07, 2023)
2-127419972-C-T		Thrombophilia due to protein C deficiency, autosomal dominant • Thrombophilia due to protein C deficiency, autosomal recessive • PROC-related disorder	Conflicting classifications of pathogenicity (Jan 24, 2024)
2-127419973-G-A		not specified	Uncertain significance (Jan 14, 2022)
2-127419981-C-T		Thrombophilia due to protein C deficiency, autosomal dominant	Likely benign (Sep 11, 2023)
2-127419983-G-A		Thrombophilia due to protein C deficiency, autosomal dominant • Reduced protein C activity	Pathogenic/Likely pathogenic (Jul 13, 2022)
2-127419993-C-T		Thrombophilia due to protein C deficiency, autosomal dominant	Likely benign (Dec 31, 2022)
2-127419994-G-A		Thrombophilia due to protein C deficiency, autosomal dominant • Thrombophilia due to protein C deficiency, autosomal dominant;Thrombophilia due to protein C deficiency, autosomal recessive	Uncertain significance (Oct 20, 2021)
2-127420002-A-G		Thrombophilia due to protein C deficiency, autosomal dominant	Likely benign (Feb 28, 2020)
2-127420008-T-C		Thrombophilia due to protein C deficiency, autosomal dominant	Benign/Likely benign (Jan 20, 2024)
2-127420011-T-C		Thrombophilia due to protein C deficiency, autosomal dominant	Uncertain significance (Jul 12, 2023)
2-127420019-C-G			Uncertain significance (Dec 07, 2021)
2-127420022-C-T		Thrombophilia due to protein C deficiency, autosomal dominant	Likely benign (Apr 06, 2023)
2-127420024-C-T		Thrombophilia due to protein C deficiency, autosomal dominant	Uncertain significance (-)
2-127420025-C-G		Thrombophilia due to protein C deficiency, autosomal dominant	Conflicting classifications of pathogenicity (May 19, 2023)
2-127421266-C-T		Thrombophilia due to protein C deficiency, autosomal dominant • PROC-related disorder	Conflicting classifications of pathogenicity (Jan 15, 2024)
2-127421267-C-A		Thrombophilia due to protein C deficiency, autosomal dominant	Likely benign (Nov 14, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PROC	protein_coding	protein_coding	ENST00000234071	8	10820

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000191	0.975	125728	0	18	125746	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.883	235	276	0.850	0.0000183	3044
Missense in Polyphen		73	102.86	0.70967		1133
Synonymous	0.722	102	112	0.913	0.00000756	863
Loss of Function	2.03	11	21.1	0.522	0.00000110	220

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000242	0.000242
Ashkenazi Jewish	0.00	0.00
East Asian	0.000274	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.0000265	0.0000264
Middle Eastern	0.000274	0.000272
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;segmentation clock;multi-step regulation of transcription by pitx2;intrinsic prothrombin activation pathway;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;Gamma-carboxylation of protein precursors;Removal of aminoterminal propeptides from gamma-carboxylated proteins;Gamma-carboxylation, transport, and amino-terminal cleavage of proteins;Gamma carboxylation, hypusine formation and arylsulfatase activation;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Intrinsic Pathway of Fibrin Clot Formation;tgf beta signaling pathway;Cell surface interactions at the vascular wall;Hemostasis;Common Pathway of Fibrin Clot Formation;Formation of Fibrin Clot (Clotting Cascade);Beta2 integrin cell surface interactions;extrinsic prothrombin activation pathway (Consensus)

Recessive Scores

• pRec: 0.657

Intolerance Scores

• loftool: 0.0970
• rvis_EVS: -0.6
• rvis_percentile_EVS: 17.91

Haploinsufficiency Scores

• pHI: 0.529
• hipred: Y
• hipred_score: 0.610
• ghis: 0.504

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.707

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Proc
• Phenotype: immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: proteolysis;endoplasmic reticulum to Golgi vesicle-mediated transport;blood coagulation;negative regulation of blood coagulation;negative regulation of apoptotic process;post-translational protein modification;cellular protein metabolic process;negative regulation of inflammatory response;negative regulation of coagulation;positive regulation of establishment of endothelial barrier
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum;endoplasmic reticulum lumen;Golgi apparatus;Golgi lumen
• Molecular function: serine-type endopeptidase activity;calcium ion binding;protein binding