PROS1

Summary

PROS1 (protein S, HGNC:9456) is a protein-coding gene on chromosome 3q11.1, encoding Vitamin K-dependent protein S (P07225). Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa.

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.

Source: NCBI Gene 5627 — RefSeq curated summary.

At a glance

• Gene–disease (curated): protein S deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 681 total — 78 pathogenic, 65 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_000313

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9456
Approved symbol	PROS1
Name	protein S
Location	3q11.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000184500
Ensembl biotype	protein_coding
OMIM	176880
Entrez	5627

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 22 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000348974, ENST00000394236, ENST00000407433, ENST00000472684, ENST00000488658, ENST00000647936, ENST00000648381, ENST00000648721, ENST00000648853, ENST00000649103, ENST00000649585, ENST00000650591, ENST00000869614, ENST00000869615, ENST00000869616, ENST00000869617, ENST00000869618, ENST00000869619, ENST00000869620, ENST00000869621, ENST00000869622, ENST00000869623, ENST00000869624, ENST00000869625, ENST00000948246, ENST00000948247, ENST00000948248

RefSeq mRNA: 2 — MANE Select: NM_000313 NM_000313, NM_001314077

CCDS: CCDS2923, CCDS93325

Canonical transcript exons

ENST00000394236 — 15 exons

Exon	Start	End
ENSE00001142392	93892933	93893122
ENSE00001291870	93873051	93874405
ENSE00001517824	93973674	93973896
ENSE00002325994	93886336	93886503
ENSE00002341788	93905784	93905915
ENSE00002343485	93896576	93896691
ENSE00002387482	93898448	93898569
ENSE00002400180	93884728	93884896
ENSE00002413512	93876966	93877191
ENSE00002414667	93879163	93879314
ENSE00002423295	93900804	93900929
ENSE00003499730	93910619	93910705
ENSE00003552504	93924240	93924264
ENSE00003576677	93927250	93927407
ENSE00003668418	93906021	93906143

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0107 / max 380.3001, expressed in 1476 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43304	12.3204	1465
43305	0.6167	391
43303	0.0636	15
43302	0.0100	5

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	99.52	gold quality
bronchial epithelial cell	CL:0002328	99.17	gold quality
synovial joint	UBERON:0002217	98.42	gold quality
epithelium of bronchus	UBERON:0002031	98.31	gold quality
bronchus	UBERON:0002185	98.17	gold quality
germinal epithelium of ovary	UBERON:0001304	98.12	gold quality
parietal pleura	UBERON:0002400	98.07	gold quality
pericardium	UBERON:0002407	97.84	gold quality
pleura	UBERON:0000977	97.77	gold quality
liver	UBERON:0002107	97.65	gold quality
dorsal root ganglion	UBERON:0000044	97.56	gold quality
visceral pleura	UBERON:0002401	97.56	gold quality
trigeminal ganglion	UBERON:0001675	97.46	gold quality
right lobe of liver	UBERON:0001114	97.42	gold quality
tibial nerve	UBERON:0001323	96.95	gold quality
ascending aorta	UBERON:0001496	96.83	gold quality
thoracic aorta	UBERON:0001515	96.83	gold quality
descending thoracic aorta	UBERON:0002345	96.72	gold quality
calcaneal tendon	UBERON:0003701	96.68	gold quality
skin of hip	UBERON:0001554	96.63	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.50	gold quality
layer of synovial tissue	UBERON:0007616	96.13	gold quality
penis	UBERON:0000989	95.94	gold quality
upper leg skin	UBERON:0004262	95.77	gold quality
tendon	UBERON:0000043	95.46	gold quality
right coronary artery	UBERON:0001625	95.46	gold quality
coronary artery	UBERON:0001621	95.27	gold quality
vena cava	UBERON:0004087	95.25	gold quality
nephron tubule	UBERON:0001231	95.16	gold quality
tibia	UBERON:0000979	95.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-2983	no	1017.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, ESR1, FOXM1, HNF1A, HNF4A, MAZ, NCOR1, NCOR2, PAX3, PGR, SP1, SP3, STAT1, STAT3

miRNA regulators (miRDB)

89 targeting PROS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-548AZ-3P	99.82	70.56	3549

Literature-anchored findings (GeneRIF, showing 40)

• The multimeric form of protein S (less than 5% of total protein S) has a 100-fold higher activated protein C-independent anticoagulant activity than the residual form (more than 95%) that binds with low affinity to phospholipids. (PMID:11467946)
• Protein S inhibits TAFI activation in two ways. (PMID:11686322)
• Heterozygozity for 4 novel missense mutations (W108C, W342R. E349K and L485S) and one novel 4 bp deletion (ACdelAAAG affecting codons 632-633) was identified in PROS1 of unrelated thrombosis-prone Danish families with protein S type I or III deficiency. (PMID:11776305)
• Pro626 in the SHBG-like domain of protein S may be crucial for the in vivo antithrombotic activity of the protein S molecule. (PMID:11843280)
• A truncated nonsense mutant protein S (Q522X)transfected into COS cells was rapidly degraded. The mutant mRNA is reduced in vivo and the protein is unstable. (PMID:11848449)
• Seven different mutations were found in 9 of 17 PS-deficient families who presented with mixed type I and type III phenotypes: delG-34 (STOP codon at -24), Val-24Glu, Arg49Cys, Asn217Ser, Gly295Val, +5 G to A intron j and His623Pro. (PMID:11858485)
• the Y595C and the K155E mutations are responsible for a secretion defect and a decreased anticoagulant activity of protein S (PMID:11927129)
• Protein S has been shown to bind to apoptotic Jurkat T cells and to mediate binding of complement regulator C4b-binding protein to apoptotic cells. (PMID:12193728)
• Molecular biological basis and diagnosis of hereditary defects (review) (PMID:12193972)
• intraindividual variation of prostate-specific antigen (PSA) isoforms in prostate cancer patients managed conservatively with watchful observation (PMID:12413608)
• Protein S is thus a multifunctional protein that can facilitate clearance of early apoptotic cells in addition to regulating blood coagulation. (PMID:12447359)
• APC-cofactor activity protein S is significantly more sensitive to structural changes in the thrombin-sensitive region than is the APC-independent activity of protein S. (PMID:12490286)
• In a multivariate analysis, only total protein S and free protein S showed significant association with seasonal change in respiratory infections after adjusting for the effect of infection. (PMID:12871408)
• complex of protein S and C4b could act as a bridge between coagulation and inflammation due to the involvement of C4BP in regulating complement activation. (PMID:12907438)
• Anti-ProtS are frequent in SLE patients with thrombosis and pregnancy morbidity. These antibodies do not interfere with free protein S in plasma since its level and/or functional activity are not impaired (PMID:14515184)
• transcription factors HNF3, MAZ, and Sp1 are required for high-level expression of the protein S gene in hepatic cells, but in non-hepatic cells such as HeLa cells, an unknown factor(s) binds to the Sp1 region and disturbs the action of Sp1 and MAZ (PMID:14652633)
• C4b-binding protein-protein S complex inhibits the phagocytosis of apoptotic cells (PMID:15096498)
• Both wt-protein S and protein S Heerlen, either free or in complex with C4BP, were equally active as prothrombinase inhibitors in the absence of APC. (PMID:15175796)
• PROS regulates coagulation at 2 levels: at low procoagulant stimuli, PROS maintains the hemostatic balance by directly inhibiting thrombin formation, and at high procoagulant stimuli, PROS restores the hemostatic balance via its APC-cofactor activity (PMID:15292065)
• Plasma-derived PROS-C4BP complex has direct anticoagulant activity; enhanced direct activity of PROS-Heerlen-C4BP may compensate for low free protein S levels and low cofactor activity in individuals with protein S-Heerlen. (PMID:15456488)
• results pinpoint exactly which transcription start sites are used for PROS and identify an indication for tissue specific regulation of PROS mRNA synthesis (PMID:15670064)
• decreased PZ and PS levels are additional risk factors for adverse pregnancy outcome (PMID:15748239)
• a protein S mutant may be degraded in the endoplasmic reticulum and have a role in protein S deficiency (PMID:15893367)
• C4BP prevents premature clearance of protein S and uses this ability to compensate the increased clearance of protein S-S460P. (PMID:16100035)
• significant elevation of anti-protein C antibodies and anti-protein S antibodies in the thrombosis group of uremia patients (PMID:16105054)
• Protein S plays a role in cell-associated plasminogen activation and invasive potential of inflammatory cells. (PMID:16229836)
• Large deletions of PROS1 are relatively common in protein S deficiency patients (PMID:16363235)
• K196E mutation is a genetic risk factor for deep vein thrombosis in Japanese patients. (PMID:16461766)
• data suggest that protein S deficiency not only increases the risk of thrombosis by impairing the protein C system but also by reducing the ability of TFPI to down-regulate the extrinsic coagulation pathway (PMID:16488980)
• In plasma from healthy individuals prothrombin levels were highly correlated to protein S levels (PMID:16493484)
• two sites most proximal to the translational start codon were found to be indispensable for PS promoter activity, whereas mutation of two most distal Sp-binding sites had a negligible influence on basal promoter activity (PMID:16672217)
• IL-6 induces Protein S expression via STAT3. Possible function for IL-6-induced Protein S expression in cell survival. (PMID:16840717)
• The PROS1 mutations would cause misfolding of the Protein S protein, resulting in the impairment of secretion, which is consistent with the type I PS deficiency phenotype. (PMID:16868938)
• All protein S deficient subjects had increased protein C/S ratios as well as a novel PROS1 c.1113T–>GG frameshift mutation. (PMID:16885060)
• annihilation of the FXa protection of the individual activated protein C-mediated Arg-506 cleavage by protein S is due to an enhanced rate of Arg-506 cleavage of FVa not bound to FXa (PMID:16935856)
• C80Y and R275C mutations affect the secretion and function of the PROS molecule, and the R314H and P375Q + D455Y mutations are responsible for only secretion defects, causing the phenotype of quantitative PS deficiency (PMID:16961607)
• protein S activity decrease is related to Behcet’s disease activity (PMID:16969634)
• Association of PROS dimorphism with plasma protein S levels in normal individuals and patients with inherited protein S deficiency was studied. (PMID:17157360)
• three different point mutations at codon 275 in the sex-hormone-binding globulin-like domain of PS were found which affected free protein S measurement (PMID:17393035)
• review of multiple functional roles of protein S and the interaction between protein S and cd4-binding protein, such as binding to apoptotoic cells, phagocytosis, anticoagulant activity (PMID:17597997)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pros1	ENSDARG00000068261
mus_musculus	Pros1	ENSMUSG00000022912
rattus_norvegicus	Pros1	ENSRNOG00000048723

Paralogs (1): SHBG (ENSG00000129214)

Protein

Protein identifiers

Vitamin K-dependent protein S — P07225 (reviewed: P07225)

All UniProt accessions (9): P07225, A0A0S2Z4K3, A0A0S2Z4L3, A0A3B3IRK9, A0A3B3ISJ1, A0A3B3ITZ7, A0A3B3IUA6, C9K0R0, G5E9F8

UniProt curated annotations — full annotation on UniProt →

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.

Subcellular location. Secreted.

Tissue specificity. Plasma.

Post-translational modifications. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_000304, NP_001301006 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000294	GLA_domain	Domain
IPR000742	EGF	Domain
IPR001791	Laminin_G	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013032	EGF-like_CS	Conserved_site
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017857	Coagulation_fac-like_Gla_dom	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR051145	GAS-SHBG-PROS	Family

Pfam: PF00054, PF00594, PF02210, PF07645, PF12661, PF14670

UniProt features (155 total): sequence variant 99, disulfide bond 15, modified residue 12, strand 8, domain 7, glycosylation site 3, mutagenesis site 2, sequence conflict 2, signal peptide 1, propeptide 1, region of interest 1, site 1, turn 1, helix 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9L20	ELECTRON MICROSCOPY	2.82
9L54	ELECTRON MICROSCOPY	3.04
1Z6C	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07225-F1	83.06	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 499 (not glycosylated; in variant heerlen)

Post-translational modifications (12): 47, 48, 55, 57, 60, 61, 66, 67, 70, 73, 77, 136

Disulfide bonds (15): 58–63, 121–134, 126–143, 145–154, 161–175, 171–184, 186–199, 205–217, 212–226, 228–241, 247–256, 252–265, 267–282, 449–475, 639–666

Glycosylation sites (3): 499, 509, 530

Mutagenesis-validated functional residues (2):

Position	Phenotype
515	markedly reduced secretion of the mutant.
515	no change in secretion of the mutant.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-159740	Gamma-carboxylation of protein precursors
R-HSA-159763	Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus
R-HSA-159782	Removal of aminoterminal propeptides from gamma-carboxylated proteins
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-9769735	Initiation of coagulation cascade
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9769743	Amplification and propagation of coagulation cascade
R-HSA-977606	Regulation of Complement cascade
R-HSA-9918485	Dengue Virus Attachment and Entry
R-HSA-9930449	Defective cleavage of FV variant at a.a.534
R-HSA-9930479	Defective cleavage of FV variant at R334
R-HSA-140837
R-HSA-140875

MSigDB gene sets: 338 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, KOBAYASHI_EGFR_SIGNALING_24HR_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_WOUND_HEALING, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GOBP_REGULATION_OF_COAGULATION, PAL_PRMT5_TARGETS_UP, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOLDRATH_IMMUNE_MEMORY, RIZKI_TUMOR_INVASIVENESS_3D_DN, STAT3_01, GOBP_NEGATIVE_REGULATION_OF_COAGULATION, GOBP_WOUND_HEALING, CEBP_Q2

GO Biological Process (4): blood coagulation (GO:0007596), fibrinolysis (GO:0042730), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), hemostasis (GO:0007599)

GO Molecular Function (3): endopeptidase inhibitor activity (GO:0004866), calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (9): Golgi membrane (GO:0000139), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	3
Coagulation pathway	3
Defective FV causes thrombophilia	2
Response to elevated platelet cytosolic Ca2+	1
Hemostasis	1
Complement cascade	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Golgi apparatus	2
cellular anatomical structure	2
hemostasis	1
wound healing	1
coagulation	1
negative regulation of blood coagulation	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of body fluid levels	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
metal ion binding	1
binding	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
platelet alpha granule	1
secretory granule lumen	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PROS1	TYRO3	Q06418	999
PROS1	MERTK	Q12866	997
PROS1	AXL	P30530	997
PROS1	GGCX	P38435	967
PROS1	C4A	P01028	953
PROS1	C4A	P01028	945
PROS1	MGP	P08493	872
PROS1	VKORC1	Q9BQB6	856
PROS1	GAS6	Q14393	819
PROS1	SERPIND1	P05546	800
PROS1	FGA	P02671	759
PROS1	SERPINC1	P01008	742
PROS1	BGLAP	P02818	741
PROS1	PROCR	Q9UNN8	718
PROS1	SOCS1	O15524	689

IntAct

95 interactions, top by confidence:

A	B	Type	Score
PROS1	HLA-A	psi-mi:“MI:0915”(physical association)	0.560
PROS1	PPIA	psi-mi:“MI:0915”(physical association)	0.560
PROS1	PRKCA	psi-mi:“MI:0915”(physical association)	0.560
PROS1	YWHAG	psi-mi:“MI:0915”(physical association)	0.560
PROS1	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
PROS1	OPTN	psi-mi:“MI:0915”(physical association)	0.560
PROS1	KAT5	psi-mi:“MI:0915”(physical association)	0.560
LMO3	PROS1	psi-mi:“MI:0915”(physical association)	0.560
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
PAEP	PROS1	psi-mi:“MI:0914”(association)	0.530
TMEM106A	B4GALT3	psi-mi:“MI:0914”(association)	0.530
rep	PROS1	psi-mi:“MI:0194”(cleavage reaction)	0.440

BioGRID (56): PROS1 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), C4BPB (Reconstituted Complex), C4BPB (Protein-peptide), PROS1 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), PROS1 (Affinity Capture-MS), PROS1 (Proximity Label-MS), PROS1 (Affinity Capture-MS), PROS1 (Reconstituted Complex), F5 (Reconstituted Complex)

ESM2 similar proteins: A0A1D5PUP4, A5YT95, O35757, O62650, O75882, O95980, P07225, P09858, P10669, P17247, P19883, P21214, P21674, P26012, P26013, P27090, P30371, P31514, P31515, P47931, P49767, P50291, P61811, P61812, P97299, P97953, Q07257, Q0VBD0, Q17QD6, Q38L25, Q5RA73, Q6NW40, Q6V9H4, Q6ZQ11, Q863H1, Q86X52, Q8BFR2, Q8CI19, Q8JG54, Q8N475

Diamond homologs: A2AR95, A2ARV4, A2VEC9, A4IHY6, A4QPB2, A6QNY1, B3EWY9, B3EWZ6, B3M8G0, B3NBB6, B4HVU2, B4L8V5, B4LCX4, B4MLE8, B4PD96, B4QMF4, B5DFC9, C0HL13, G3V928, G4NGN5, O88322, P01130, P07225, P10493, P14543, P15306, P35950, P35951, P35952, P35953, P53813, P86091, P98155, P98157, P98158, P98163, P98164, P98165, P98167, Q00968

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GGCX	“up-regulates activity”	PROS1	carboxylation
PROS1	up-regulates	AXL	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

681 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	78
Likely pathogenic	65
Uncertain significance	280
Likely benign	169
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048664	NM_000313.4(PROS1):c.740G>C (p.Cys247Ser)	Pathogenic
1066657	NM_000313.4(PROS1):c.1A>C (p.Met1Leu)	Pathogenic
1068259	NM_000313.4(PROS1):c.1871-2A>G	Pathogenic
1069092	NM_000313.4(PROS1):c.1084C>T (p.Gln362Ter)	Pathogenic
1069702	NM_000313.4(PROS1):c.181G>T (p.Glu61Ter)	Pathogenic
1330283	NM_000313.4(PROS1):c.1870+1G>C	Pathogenic
1330284	NM_000313.4(PROS1):c.76+2_76+3del	Pathogenic
13317	NM_000313.4(PROS1):c.773A>G (p.Asn258Ser)	Pathogenic
13318	NM_000313.4(PROS1):c.586A>G (p.Lys196Glu)	Pathogenic
13319	PROS1, IVS10DS, G-A, +5	Pathogenic
13320	NM_000313.4(PROS1):c.2031A>T (p.Ter677Tyr)	Pathogenic
13321	NM_000313.4(PROS1):c.1324-9A>G	Pathogenic
13322	NM_000313.4(PROS1):c.835C>T (p.Gln279Ter)	Pathogenic
1389448	NM_000313.4(PROS1):c.820A>T (p.Lys274Ter)	Pathogenic
1406689	NM_000313.4(PROS1):c.1871-1G>A	Pathogenic
1410953	NM_000313.4(PROS1):c.793dup (p.Cys265fs)	Pathogenic
1452101	NM_000313.4(PROS1):c.3G>C (p.Met1Ile)	Pathogenic
1454860	NC_000003.11:g.(?93605147)(93617433_?)del	Pathogenic
1456211	NM_000313.4(PROS1):c.864C>A (p.Cys288Ter)	Pathogenic
1457418	NC_000003.11:g.(?93629453)(93692783_?)del	Pathogenic
1684341	NM_000313.4(PROS1):c.1764_1765del (p.Pro589fs)	Pathogenic
1684343	NM_000313.4(PROS1):c.139G>T (p.Glu47Ter)	Pathogenic
1684424	NM_000313.4(PROS1):c.-39C>T	Pathogenic
1901307	NM_000313.4(PROS1):c.760C>T (p.Gln254Ter)	Pathogenic
1999459	NM_000313.4(PROS1):c.1977del (p.Asn659fs)	Pathogenic
216868	NM_000313.4(PROS1):c.967delinsGG (p.Phe323fs)	Pathogenic
219837	NM_000313.4(PROS1):c.1681C>T (p.Arg561Trp)	Pathogenic
2203406	NM_000313.4(PROS1):c.1518G>A (p.Trp506Ter)	Pathogenic
2694232	NM_000313.4(PROS1):c.1A>G (p.Met1Val)	Pathogenic
2731141	NM_000313.4(PROS1):c.77-2A>G	Pathogenic

SpliceAI

2558 predictions. Top by Δscore:

Variant	Effect	Δscore
3:93874402:ACAT:A	acceptor_gain	1.0000
3:93874403:CAT:C	acceptor_gain	1.0000
3:93874403:CATC:C	acceptor_gain	1.0000
3:93874404:AT:A	acceptor_gain	1.0000
3:93874404:ATCT:A	acceptor_loss	1.0000
3:93874405:TC:T	acceptor_loss	1.0000
3:93874406:C:CC	acceptor_gain	1.0000
3:93876962:ATAC:A	donor_loss	1.0000
3:93876964:A:T	donor_loss	1.0000
3:93876965:C:G	donor_loss	1.0000
3:93879158:GTTA:G	donor_loss	1.0000
3:93879159:TTA:T	donor_loss	1.0000
3:93879160:TAC:T	donor_loss	1.0000
3:93879161:A:AT	donor_loss	1.0000
3:93879311:TTAT:T	acceptor_gain	1.0000
3:93879314:TCTA:T	acceptor_loss	1.0000
3:93879315:C:CC	acceptor_gain	1.0000
3:93879315:C:CG	acceptor_loss	1.0000
3:93879319:T:C	acceptor_gain	1.0000
3:93884724:TTA:T	donor_loss	1.0000
3:93884725:TACTA:T	donor_loss	1.0000
3:93884726:A:AC	donor_gain	1.0000
3:93884726:A:C	donor_loss	1.0000
3:93884727:C:CT	donor_gain	1.0000
3:93884727:CT:C	donor_gain	1.0000
3:93884727:CTA:C	donor_gain	1.0000
3:93884727:CTAT:C	donor_gain	1.0000
3:93884727:CTATA:C	donor_gain	1.0000
3:93884892:TTAAT:T	acceptor_gain	1.0000
3:93884893:TAAT:T	acceptor_gain	1.0000

AlphaMissense

4457 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:93927296:C:G	C63S	0.996
3:93927297:A:T	C63S	0.996
3:93927311:C:G	C58S	0.996
3:93927312:A:T	C58S	0.996
3:93906089:C:G	C134S	0.994
3:93906090:A:T	C134S	0.994
3:93905903:C:G	C161S	0.992
3:93905904:A:T	C161S	0.992
3:93906043:C:A	W149C	0.992
3:93906043:C:G	W149C	0.992
3:93927269:A:C	F72C	0.992
3:93927312:A:G	C58R	0.992
3:93905861:C:G	C175S	0.991
3:93905862:A:T	C175S	0.991
3:93906128:C:G	C121S	0.991
3:93906129:A:T	C121S	0.991
3:93893099:C:G	R330P	0.990
3:93906062:C:G	C143S	0.990
3:93906063:A:T	C143S	0.990
3:93910703:A:G	C88R	0.990
3:93927296:C:T	C63Y	0.990
3:93927297:A:G	C63R	0.990
3:93927310:G:C	C58W	0.990
3:93874360:C:G	C639S	0.989
3:93874361:A:T	C639S	0.989
3:93884874:C:G	C449S	0.989
3:93884875:A:T	C449S	0.989
3:93898497:C:G	C267S	0.989
3:93898498:A:T	C267S	0.989
3:93905789:C:G	C199S	0.989

dbSNP variants (sampled 300 via entrez): RS1000010298 (3:93967275 T>C,G), RS1000028072 (3:93961016 T>C), RS1000065236 (3:93948323 A>G), RS1000070680 (3:93932395 C>T), RS1000093692 (3:93888535 T>C), RS1000130908 (3:93945723 G>A), RS1000180836 (3:93906301 C>T), RS1000316957 (3:93961400 T>C), RS1000323051 (3:93950944 AG>A), RS1000355762 (3:93912568 C>A), RS1000403862 (3:93881251 G>A), RS1000476739 (3:93955814 G>A,C), RS1000494039 (3:93932107 C>T), RS1000577971 (3:93936250 T>C), RS1000670099 (3:93900148 C>A)

Disease associations

OMIM: gene MIM:176880 | disease phenotypes: MIM:612336, MIM:614514, MIM:256300, MIM:612291

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombophilia due to protein S deficiency, autosomal dominant	Definitive	Autosomal dominant
thrombophilia due to protein S deficiency, autosomal recessive	Definitive	Autosomal recessive
protein S deficiency	Definitive	Semidominant
hereditary thrombophilia due to congenital protein S deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
protein S deficiency	Definitive	SD

Mondo (9): thrombophilia due to protein S deficiency, autosomal dominant (MONDO:0012868), thrombophilia due to protein S deficiency, autosomal recessive (MONDO:0013791), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), hereditary thrombophilia due to congenital protein S deficiency (MONDO:0019144), protein S deficiency (MONDO:0002304), congenital nephrotic syndrome, Finnish type (MONDO:0009732), thrombocytopenia (MONDO:0002049), Joubert syndrome 8 (MONDO:0012855)

Orphanet (5): Protein S acquired deficiency (Orphanet:26349), Severe hereditary thrombophilia due to congenital protein S deficiency (Orphanet:743), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Congenital nephrotic syndrome, Finnish type (Orphanet:839), Isolated Joubert syndrome (Orphanet:475)

HPO phenotypes

27 total (28 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000488	Retinopathy
HP:0000618	Blindness
HP:0000963	Thin skin
HP:0000979	Purpura
HP:0001000	Abnormality of skin pigmentation
HP:0001038	Warfarin-induced skin necrosis
HP:0001250	Seizure
HP:0001342	Cerebral hemorrhage
HP:0001903	Anemia
HP:0001933	Subcutaneous hemorrhage
HP:0002204	Pulmonary embolism
HP:0002625	Deep venous thrombosis
HP:0002638	Superficial thrombophlebitis
HP:0003623	Neonatal onset
HP:0004418	Thrombophlebitis
HP:0004420	Arterial thrombosis
HP:0004855	Reduced protein S activity
HP:0005293	Venous insufficiency
HP:0005305	Cerebral venous thrombosis
HP:0005521	Disseminated intravascular coagulation
HP:0008065	Aplasia/Hypoplasia of the skin
HP:0100659	Abnormal cerebral vascular morphology
HP:0100724	Hypercoagulability
HP:0100758	Gangrene
HP:0200042	Skin ulcer
HP:0000556	Retinal dystrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005752_23	Systemic lupus erythematosus	5.000000e-07

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D018455	Protein S Deficiency	C15.378.100.800; C15.378.147.890; C15.378.925.800
D058499	Retinal Dystrophies	C11.768.585.658
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C567077	Acquired Protein S Deficiency (supp.)
C567358	Joubert Syndrome 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5498501 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8178607	PROS1		0.00	0

CTD chemical–gene interactions

86 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Ethinyl Estradiol	decreases expression, decreases activity, increases expression, affects cotreatment, affects expression	10
Gestodene	affects expression, decreases activity, decreases expression, increases expression, affects cotreatment	7
ethinyl estradiol-desogestrel combination	decreases activity, decreases expression	7
Valproic Acid	increases expression, decreases expression, affects cotreatment	5
Cyclosporine	affects cotreatment, affects expression, decreases expression	5
Acetaminophen	decreases expression	3
Estradiol	decreases expression, increases expression, affects cotreatment	3
Tobacco Smoke Pollution	decreases expression	3
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Cisplatin	affects expression, affects response to substance	2
Contraceptives, Oral	decreases activity, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tamoxifen	affects expression, decreases expression	2
Tretinoin	increases expression	2
Levonorgestrel	decreases expression, affects cotreatment, decreases activity	2
Thapsigargin	decreases expression	2
Raloxifene Hydrochloride	decreases expression, affects expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
tungsten carbide	affects binding, decreases expression	1
testosterone enanthate	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
deoxynivalenol	decreases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
norgestimate	affects cotreatment, decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TH19	HAP1 PROS1 (-) 1	Cancer cell line	Male
CVCL_TH20	HAP1 PROS1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

291 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT