PROS1

protein S, the group of Gla domain containing

Basic information

Region (hg38): 3:93873051-93980003

Previous symbols: [ "PROS" ]

Links

ENSG00000184500 ∙ NCBI:5627 ∙ OMIM:176880 ∙ HGNC:9456 ∙ Uniprot:P07225 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thrombophilia due to protein S deficiency, autosomal dominant (Strong), mode of inheritance: AD
• thrombophilia due to protein S deficiency, autosomal recessive (Strong), mode of inheritance: AR
• thrombophilia due to protein S deficiency, autosomal dominant (Definitive), mode of inheritance: Semidominant
• hereditary thrombophilia due to congenital protein S deficiency (Supportive), mode of inheritance: AR
• thrombophilia due to protein S deficiency, autosomal dominant (Strong), mode of inheritance: AD
• thrombophilia due to protein S deficiency, autosomal recessive (Strong), mode of inheritance: AR
• hereditary thrombophilia due to congenital protein S 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 S deficiency	AD/AR	Hematologic	Individuals may be at higher risk for thrombophilia, and may demonstrate thrombosis and secondary hemorrhage usually beginning in early infancy (in recessive forms); Prompt recognition may allow preventive measures and early treament, which may reduce morbidity and mortality	Hematologic	6239102; 6238642; 2952034; 2935209; 2231208; 2141197; 7899424; 7545463; 10442899; 10063989; 19168201; 19466456; 19826897; 20398916; 20484936; 20484936; 21172841; 21799399; 22166512

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PROS1 gene.

• Thrombophilia due to protein S deficiency, autosomal recessive (35 variants)
• Thrombophilia due to protein S deficiency, autosomal dominant (8 variants)
• not provided (5 variants)
• Protein S deficiency disease (4 variants)
• PROS1-related disorder (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PROS1 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			1	60	2	63
missense	8	24	141			173
nonsense	15	5				20
start loss	3					3
frameshift	11	7	1			19
inframe indel	1					1
splice donor/acceptor (+/-2bp)	8	13	1			22
splice region		1	10	14	1	26
non coding		1	37	38	12	88
Total	46	50	181	98	14

Highest pathogenic variant AF is 0.0000460

Variants in PROS1

This is a list of pathogenic ClinVar variants found in the PROS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-93873059-G-A		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873074-TCAAA-T		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jun 14, 2016)
3-93873106-G-T		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873142-T-C		Thrombophilia due to protein S deficiency, autosomal dominant • Thrombophilia due to protein S deficiency, autosomal dominant;Thrombophilia due to protein S deficiency, autosomal recessive	Uncertain significance (Aug 17, 2021)
3-93873163-T-C		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873199-A-G		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873231-A-G		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873253-A-C		Thrombophilia due to protein S deficiency, autosomal dominant	Likely benign (Jan 13, 2018)
3-93873273-G-A		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873358-G-T		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 12, 2018)
3-93873462-G-A		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873508-C-G		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 12, 2018)
3-93873531-A-G		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873552-C-T		Thrombophilia due to protein S deficiency, autosomal dominant • Thrombophilia due to protein S deficiency, autosomal dominant;Thrombophilia due to protein S deficiency, autosomal recessive	Uncertain significance (Feb 01, 2022)
3-93873559-C-T		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 12, 2018)
3-93873695-C-T		Thrombophilia due to protein S deficiency, autosomal dominant • Thrombophilia due to protein S deficiency, autosomal dominant;Thrombophilia due to protein S deficiency, autosomal recessive	Uncertain significance (Sep 08, 2021)
3-93873725-T-G		Thrombophilia due to protein S deficiency, autosomal dominant	Benign (Mar 06, 2018)
3-93873776-T-G		Thrombophilia due to protein S deficiency, autosomal dominant	Likely benign (Jan 13, 2018)
3-93873791-C-T		Thrombophilia due to protein S deficiency, autosomal dominant	Likely benign (Jan 13, 2018)
3-93873823-C-A		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 12, 2018)
3-93873860-T-C		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 13, 2018)
3-93873865-T-A		Thrombophilia due to protein S deficiency, autosomal dominant	Likely benign (Jan 12, 2018)
3-93873875-C-T		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jun 14, 2016)
3-93873944-T-C		Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Jan 12, 2018)
3-93874023-AT-A		Thrombophilia due to protein S deficiency, autosomal dominant • Thrombophilia due to protein S deficiency, autosomal recessive;Thrombophilia due to protein S deficiency, autosomal dominant	Uncertain significance (Sep 01, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PROS1	protein_coding	protein_coding	ENST00000394236	15	101030

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000471	0.999	125730	0	18	125748	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.585	335	366	0.914	0.0000186	4443
Missense in Polyphen		89	129.27	0.68849		1607
Synonymous	0.110	129	131	0.988	0.00000667	1266
Loss of Function	3.49	12	34.0	0.353	0.00000153	454

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000616	0.0000615
Ashkenazi Jewish	0.0000995	0.0000992
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000884	0.0000879
Middle Eastern	0.000109	0.000109
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis.
• Disease: DISEASE: Thrombophilia due to protein S deficiency, autosomal dominant (THPH5) [MIM:612336]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. Based on the plasma levels of total and free PROS1 as well as the serine protease-activated protein C cofactor activity, three types of THPH5 have been described: type I, characterized by reduced total and free PROS1 levels together with reduced anticoagulant activity; type III, in which only free PROS1 antigen and PROS1 activity levels are reduced; and the rare type II which is characterized by normal concentrations of both total and free PROS1 antigen, but low cofactor activity. {ECO:0000269|PubMed:10447256, ECO:0000269|PubMed:10613647, ECO:0000269|PubMed:10706858, ECO:0000269|PubMed:10790208, ECO:0000269|PubMed:11372770, ECO:0000269|PubMed:11776305, ECO:0000269|PubMed:11858485, ECO:0000269|PubMed:11927129, ECO:0000269|PubMed:12351389, ECO:0000269|PubMed:12632031, ECO:0000269|PubMed:15238143, ECO:0000269|PubMed:15712227, ECO:0000269|PubMed:18322254, ECO:0000269|PubMed:7482398, ECO:0000269|PubMed:7545463, ECO:0000269|PubMed:7579449, ECO:0000269|PubMed:7803790, ECO:0000269|PubMed:8298131, ECO:0000269|PubMed:8639833, ECO:0000269|PubMed:8701404, ECO:0000269|PubMed:8765219, ECO:0000269|PubMed:8781426, ECO:0000269|PubMed:8943854, ECO:0000269|PubMed:8977443, ECO:0000269|PubMed:9031443, ECO:0000269|PubMed:9241758, ECO:0000269|Ref.15}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thrombophilia due to protein S deficiency, autosomal recessive (THPH6) [MIM:614514]: A very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage. {ECO:0000269|PubMed:20484936}. 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;Human Complement System;Dengue-2 Interactions with Complement and Coagulation Cascades;Complement and Coagulation Cascades;intrinsic prothrombin activation pathway;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;Innate Immune System;Immune System;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Cell surface interactions at the vascular wall;Hemostasis;Common Pathway of Fibrin Clot Formation;Formation of Fibrin Clot (Clotting Cascade);Regulation of Complement cascade;Complement cascade;extrinsic prothrombin activation pathway (Consensus)

Recessive Scores

• pRec: 0.427

Intolerance Scores

• loftool: 0.270
• rvis_EVS: -0.22
• rvis_percentile_EVS: 37.6

Haploinsufficiency Scores

• pHI: 0.117
• hipred: N
• hipred_score: 0.466
• ghis: 0.532

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.457

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pros1
• 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); embryo phenotype; liver/biliary system phenotype; normal phenotype; 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; muscle phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: platelet degranulation;endoplasmic reticulum to Golgi vesicle-mediated transport;blood coagulation;negative regulation of endopeptidase activity;regulation of complement activation;fibrinolysis;leukocyte migration
• Cellular component: Golgi membrane;extracellular region;extracellular space;endoplasmic reticulum membrane;Golgi lumen;plasma membrane;platelet alpha granule lumen;extracellular exosome;blood microparticle
• Molecular function: endopeptidase inhibitor activity;calcium ion binding