PROS1

Chr 3ADAR

protein S

Also known as: PROS, PS21, PS22, PS23, PS24, PS25, PSA, THPH5

NCBI Gene: 5627ENSG00000184500UniProt: P07225

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]

Primary Disease Associations & Inheritance

Thrombophilia 5 due to protein S deficiency, autosomal dominantMIM #612336
AD
Thrombophilia 5 due to protein S deficiency, autosomal recessiveMIM #614514
AR
UniProtThrombophilia due to protein S deficiency, autosomal dominant
UniProtThrombophilia due to protein S deficiency, autosomal recessive
491
ClinVar variants
121
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— PROS1
🧬
Gene-Disease Validity (ClinGen)
protein S deficiency · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
121 Pathogenic / Likely Pathogenic· 212 VUS of 491 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.57LOEUF
pLI 0.000
Z-score 3.49
OE 0.35 (0.23–0.57)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.58Z-score
OE missense 0.91 (0.83–1.00)
335 obs / 366.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.35 (0.23–0.57)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.83–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 12 / 34.0Missense obs/exp: 335 / 366.5Syn Z: 0.11

ClinVar Variant Classifications

491 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61
Likely Pathogenic60
VUS212
Likely Benign112
Benign9
Conflicting37
61
Pathogenic
60
Likely Pathogenic
212
VUS
112
Likely Benign
9
Benign
37
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
8
34
0
61
Likely Pathogenic
25
21
14
0
60
VUS
3
150
56
3
212
Likely Benign
0
1
60
51
112
Benign
0
0
7
2
9
Conflicting
—37
Total4718017156491

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PROS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
PROTEIN S; PROS1
MIM #176880 · *

Thrombophilia 5 due to protein S deficiency, autosomal dominant

MIM #612336

Molecular basis of disorder known

Autosomal dominant

Thrombophilia 5 due to protein S deficiency, autosomal recessive

MIM #614514

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PROS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.
Stefanucci L et al.·Blood
2023
PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma.
Wang J et al.·Front Immunol
2023
Population-Scale Studies of Protein S Abnormalities and Thrombosis.
Chaudhry SA et al.·JAMA
2025
PROS1-MERTK Axis Drives Tumor Microenvironment Crosstalk and Progression in Papillary Thyroid Microcarcinoma.
Zhang W et al.·Adv Sci (Weinh)
2025
Classic Thrombophilias and Thrombotic Risk Among Middle-Aged and Older Adults: A Population-Based Cohort Study.
Manderstedt E et al.·J Am Heart Assoc
2022Cohort
PROS1 is a crucial gene in the macrophage efferocytosis of diabetic foot ulcers: a concerted analytical approach through the prisms of computer analysis.
Shi H et al.·Aging (Albany NY)
2024
Mechanistic insights into PROS1 inhibition of bladder cancer progression and angiogenesis via the AKT/GSK3β/β-catenin pathway.
Fan XP et al.·Sci Rep
2025
PROS1, a clinical prognostic biomarker and tumor suppressor, is associated with immune cell infiltration in breast cancer: A bioinformatics analysis combined with experimental verification.
He T et al.·Cell Signal
2023
In Situ Proefferocytosis Microspheres as Macrophage Polarity Converters Accelerate Osteoarthritis Treatment.
Wang Y et al.·Small
2025
Diagnosing protein S deficiency - Navigating challenges.
Hansen RS et al.·Clin Biochem
2025Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
PROS1/AXL signaling protects mice from lethal influenza infection by inducing M2 macrophage polarization.
Zhu W et al.·Acta Biochim Biophys Sin (Shanghai)
2025
PROS1 released by lung basal cells limits inflammation in epithelial and monocytes during SARS-CoV-2 infection.
Simakou T et al.·Discov Immunol
2025🔓 Open Access
Recurrent ischemic strokes caused by hereditary protein S deficiency from a novel PROS1 mutation: a case report.
Huang MY et al.·BMC Neurol
2025🔓 Open AccessCase report
Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation.
Fabiano MP et al.·Cell Rep
2025
PROS1 (Cys228Tyr) missense mutation associated with mesenteric and pulmonary venous thromboembolism during the COVID-19 pandemic: a case report.
Huang J et al.·Front Cardiovasc Med
2025🔓 Open AccessCase report
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Lung CancerNSCLC

Modulatory Effect of Prodigiosin or Pioglitazone on TIME and the Crosstalk to Immune-Checkpoint Protein(s)

NOT YET RECRUITING
NCT06502249Ain Shams UniversityStarted 2026-06
Pregnancy ComplicationsPre-EclampsiaGrowth Retardation, Intrauterine

Autophagy/Apoptosis Balance in Placental Vascular Pathologies

RECRUITING
NCT06779916Centre Hospitalier Universitaire de NīmesStarted 2025-05-02
Blood testUrine test
Congenital Adrenal Hyperplasia (CAH)

Fertility And Sexual Function In CAH: CALLIOPE

RECRUITING
NCT07099456University of Roma La SapienzaStarted 2024-11-01

External Resources

Links to major genomics databases and tools