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

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Thrombophilia, hereditary, due to protein S deficiencyAD/ARHematologicIndividuals 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 mortalityHematologic6239102; 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 (412 variants)
  • Thrombophilia_due_to_protein_S_deficiency,_autosomal_dominant (126 variants)
  • not_provided (91 variants)
  • Inborn_genetic_diseases (49 variants)
  • Protein_S_deficiency_disease (44 variants)
  • PROS1-related_disorder (37 variants)
  • Retinal_dystrophy (9 variants)
  • not_specified (4 variants)
  • Hereditary_thrombophilia_due_to_congenital_protein_S_deficiency (3 variants)
  • Abnormal_bleeding (2 variants)
  • Optic_atrophy (2 variants)
  • Thromboembolism (2 variants)
  • Thrombocytopenia (1 variants)
  • Incidental_Discovery (1 variants)
  • Finnish_congenital_nephrotic_syndrome (1 variants)
  • Abnormal_thrombosis (1 variants)
  • Deep_venous_thrombosis (1 variants)
  • Protein_S_Heerlen (1 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. These statistics are base on transcript: NM_000000313.4. Only rare variants are included in the table.

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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
8
clinvar
92
clinvar
1
clinvar
 102
missense
11
clinvar
47
clinvar
219
clinvar
11
clinvar
 288
nonsense
23
clinvar
6
clinvar
 29
start loss
3
1
4
frameshift
18
clinvar
12
clinvar
2
clinvar
 32
splice donor/acceptor (+/-2bp)
10
clinvar
21
clinvar
5
clinvar
 36
Total 65 88 234 103 1

Highest pathogenic variant AF is 0.0005702668

Loading clinvar variants...

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
PROS1protein_codingprotein_codingENST00000394236 15101030
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
1257300181257480.0000716
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense0.5853353660.9140.00001864443
Missense in Polyphen89129.270.688491607
Synonymous0.1101291310.9880.000006671266
Loss of Function3.491234.00.3530.00000153454

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.00006160.0000615
Ashkenazi Jewish0.00009950.0000992
East Asian0.0001090.000109
Finnish0.000.00
European (Non-Finnish)0.00008840.0000879
Middle Eastern0.0001090.000109
South Asian0.0001310.000131
Other0.000.00

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

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

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
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