GeneBe

PROS1

protein-coding

protein S, the group of Gla domain containing

Gene summary

This gene encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Mutations in this gene result in autosomal dominant hereditary thrombophilia. An inactive pseudogene of this locus is located at an adjacent region on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Oct 2015]

Previous symbols:
  • PROS

MANE transcript

NM_000313.4

Inheritance

AR, SD, AD

ClinVar variants

P:167U:267B:109

Top phenotype

Thrombophilia, hereditary, due to protein S deficiency

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr3:93,873,051-93,980,003

External References & Databases

Ensembl (ENSG00000184500)NCBI Gene (5627)OMIM (176880)HGNC:9456GenCCUniProt (P07225)AlphaFoldClinVar (PROS1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~107.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary thrombophilia due to congenital protein S deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019144

Submitter: Orphanet

thrombophilia due to protein S deficiency, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013791

Submitter: Labcorp Genetics (formerly Invitae)

thrombophilia due to protein S deficiency, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013791

Submitter: Ambry Genetics

protein S deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0002304

Submitter: ClinGen

PROS1 was first reported in relation to semidominant protein S deficiency in 1994 (Hayashi T, et al., 1994, PMID: 8298131). Over 400 unique variants (including missense, nonsense, splicing and frameshift variants) 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 18 probands in 5 publications (PMIDs: 8298131, 10063989, 7545463, 20484936, 10447256). Variants in this gene segregated with disease in 33 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 as a cofactor for Protein C (PMID: 6892911), and both heterozygous and null mouse models which recapitulate phenotypes observed in humans (PMID: 19567881). In summary, PROS1 is definitively associated with semidominant protein S deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

thrombophilia due to protein S deficiency, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012868

Submitter: PanelApp Australia

thrombophilia due to protein S deficiency, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013791

Submitter: PanelApp Australia

thrombophilia due to protein S deficiency, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012868

Submitter: Genomics England PanelApp

thrombophilia due to protein S deficiency, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013791

Submitter: Genomics England PanelApp

thrombophilia due to protein S deficiency, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012868

Submitter: Labcorp Genetics (formerly Invitae)

thrombophilia due to protein S deficiency, autosomal dominantDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0012868

Submitter: Ambry Genetics

thrombophilia due to protein S deficiency, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012868

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Thrombophilia, hereditary, due to protein S deficiencyAD/AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: 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

Refs: 6239102; 6238642; 2952034; 2935209; 2231208; 2141197; 7899424; 7545463; 10442899; 10063989; 19168201; 19466456; 19826897; 20398916; 20484936; 20484936; 21172841; 21799399; 22166512Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PROS1 variants in ClinVar

19 Conditions Cataloged
Thrombophilia due to protein S deficiency, autosomal recessiveTotal: 424
Thrombophilia due to protein S deficiency, autosomal dominantTotal: 161
not providedTotal: 104
PROS1-related disorderTotal: 65
Inborn genetic diseasesTotal: 60
Protein S deficiency diseaseTotal: 43
not specifiedTotal: 18
Retinal dystrophyTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000313.4. 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
1
clinvar
8
clinvar
95
clinvar
1
clinvar
 105
missense
8
clinvar
53
clinvar
253
clinvar
13
clinvar
 327
nonsense
23
clinvar
7
clinvar
 30
start loss
3
clinvar
1
clinvar
 4
frameshift
18
clinvar
19
clinvar
2
clinvar
 39
splice donor/acceptor (+/-2bp)
10
clinvar
24
clinvar
4
clinvar
 38
Total621052671081543

Highest pathogenic variant AF is 0.0005702668

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000313.4RefSeqNP_000304.215MANE Select
ENST00000394236.9EnsemblENSP00000377783.315MANE Select
NM_001314077.2RefSeqNP_001301006.116Standard
ENST00000348974.5EnsemblENSP00000330021.715Standard

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
  • Human Complement System
  • Dengue-2 Interactions with Complement and Coagulation Cascades
  • Complement and Coagulation Cascades

Biological Process

  • platelet degranulation
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • blood coagulation
  • negative regulation of endopeptidase activity
  • regulation of complement activation

Molecular Function

  • endopeptidase inhibitor activity
  • calcium ion binding

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000394236
Coding exons
15
Length
101030
Individuals with no LoFs
125730
Homozygous LoFs
0
Heterozygous LoFs
18
Defined
125748
p
0.0000716
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.5853353660.9140.00001864443
Missense (PolyPhen)89129.270.688491607
Synonymous0.1101291310.9880.000006671266
Loss of Function3.491234.00.3530.00000153454

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000100.000099rare
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000880.000088rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.427

Intolerance Scores

LoFtool
0.270
RVIS EVS
-0.22
RVIS percentile EVS
37.6

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.457

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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