rs121918473 — PROS1 Asn258Ser

Protein S Deficiency — When the Anticoagulant Brake Fails

Protein S is a vitamin K-dependent plasma glycoprotein that acts as an essential cofactor for activated protein C (APC)¹¹ activated protein C (APC)
Activated protein C is the central anticoagulant enzyme; it inactivates clotting factors Va and VIIIa to brake the coagulation cascade. Without adequate protein S, the APC system loses efficiency, and the body's ability to brake clot formation is compromised. The rs121918473 variant in the PROS1 gene — encoding the p.Asn258Ser substitution — was first identified in 1995 by Formstone and colleagues²² first identified in 1995 by Formstone and colleagues
In a pedigree with autosomal dominant protein S deficiency, using RT-PCR mutation screening as a cause of familial autosomal dominant thrombophilia. It is classified as pathogenic by ClinVar (VCV000013317) and is catalogued in OMIM as allelic variant 176880.0002.

Because this variant is so rare — absent in 594,524 gnomAD exome samples — it is not a common population polymorphism but a rare disease allele³³ rare disease allele
Most functional PROS1 disease variants are private or found only in small family pedigrees; the rarity makes population frequency estimates unreliable that is identified in clinical or research sequencing of families with unexplained thrombophilia.

The Mechanism

The PROS1 gene on chromosome 3 is transcribed from the minus strand. The rs121918473 variant creates an A>G transition in the coding sequence (NM_000313.4:c.773A>G), which on the plus strand corresponds to a T>C change at position 93,898,524 (GRCh38). The resulting amino acid substitution — asparagine to serine at position 258 (p.Asn258Ser) — falls within the fourth EGF-like domain of protein S⁴⁴ fourth EGF-like domain of protein S
Protein S contains four tandem EGF-like domains (residues 178–345) that mediate binding to activated protein C and phospholipid surfaces; the fourth domain is critical for cofactor activity.

Loss of asparagine at position 258 likely disrupts local domain folding or glycosylation, impairing protein S secretion or cofactor function. Heterozygous carriers produce only one functional PROS1 allele, resulting in reduced free protein S levels consistent with type I protein S deficiency⁵⁵ type I protein S deficiency
Type I (quantitative): both total and free protein S antigen levels are reduced, typically to 40–60% of normal in heterozygotes; type II is functional deficiency with normal antigen levels; type III has selectively reduced free protein S. Approximately 95% of protein S-deficient patients have type I or type III deficiency; missense variants like p.Asn258Ser typically cause type I.

The Evidence

The clearest quantification of risk from high-impact PROS1 variants comes from a 2025 population-scale study in JAMA⁶⁶ 2025 population-scale study in JAMA
Chaudhry et al., using UK Biobank and All of Us, n > 500,000: carriers of the most damaging PROS1 variants have protein S levels at 48% of normal and face an odds ratio of 14.01 (95% CI 6.98–27.14) for venous thromboembolism. A meta-analysis of 14 observational studies⁷⁷ meta-analysis of 14 observational studies
Di Minno et al., 4,955 VTE cases and 9,267 controls estimated OR 5.37 (95% CI 2.70–10.67) for a first VTE event across protein S-deficient individuals broadly, with broader uncertainty at the low end reflecting population heterogeneity.

A Danish clinical cohort⁸⁸ Danish clinical cohort
Larsen et al. 2021, n=22 PROS1 index cases found VTE frequency of 43% among PROS1 variant carriers versus 17% in those with normal PROS1 sequence (p=0.05), with significantly lower free protein S levels (0.51 vs 0.62 × 10³ IU/L) among carriers.

Protein S deficiency is not purely a venous thrombosis risk. A meta-analysis of inherited thrombophilias and arterial stroke⁹⁹ meta-analysis of inherited thrombophilias and arterial stroke
Chiasakul et al. 2019 found OR 2.26 (95% CI 1.34–3.80) for arterial ischemic stroke in protein S-deficient individuals, though the mechanism (paradoxical clot embolism vs. direct arterial effects) is less well understood.

For women, the interaction with combined hormonal contraceptives is critical: severe thrombophilias including protein S deficiency combined with oral contraceptive use carry RR 7.15 (95% CI 2.93–17.45)¹⁰¹⁰ RR 7.15 (95% CI 2.93–17.45)
van Vlijmen et al. 2016 systematic review, absolute risk 4.3–4.6 VTE events per 100 pill-years for VTE, representing a contraindication to estrogen-containing methods. Pregnancy itself carries a postpartum absolute risk of 4.2% (95% CrI 0.7–9.4%) for a first VTE event in protein S-deficient women per a Bayesian meta-analysis¹¹¹¹ Bayesian meta-analysis
Croles et al. 2017, BMJ.

Practical Implications

Because this is a pathogenic variant causing autosomal dominant thrombophilia, the clinical implications are immediate and concrete. First, free protein S levels should be measured to confirm biochemical deficiency and guide clinical classification. Second, all estrogen-containing hormonal preparations — combined oral contraceptives, patches, rings, and menopausal hormone therapy — are contraindicated. Third, standard surgical and perioperative thromboprophylaxis applies, with disclosure to all treating providers before any procedure. Fourth, anticoagulation after a first VTE event is managed in consultation with a hematologist, with particular attention to whether indefinite anticoagulation is warranted.

Direct oral anticoagulants (DOACs: rivaroxaban, apixaban, dabigatran) are the modern standard for thromboprophylaxis and treatment in most thrombophilia patients, though an ISTH SSC communication¹²¹² ISTH SSC communication
Kovac et al. 2024 notes that treatment failure risk is elevated in severe protein S deficiency (levels below 20%), warranting specialist management in those cases.

Interactions

The most clinically important interaction is with Factor V Leiden (rs6025, F5 R506Q)¹³¹³ Factor V Leiden (rs6025, F5 R506Q)
The most common inherited thrombophilia in Europeans (~5% carrier frequency); FVL prevents APC from inactivating factor Va — a complementary defect to protein S deficiency, which impairs APC cofactor activity. Simultaneous deficiency of protein S (impairing APC cofactor activity) and Factor V Leiden (making factor Va resistant to APC inactivation) attacks the same anticoagulant pathway at two separate points, compounding VTE risk substantially — likely exceeding the risk of either defect alone.

Similarly, Prothrombin G20210A (rs1799963, F2)¹⁴¹⁴ Prothrombin G20210A (rs1799963, F2)
Second most common inherited thrombophilia; raises prothrombin levels 30%, increasing substrate for thrombin generation would compound with protein S deficiency by simultaneously elevating the pro-coagulant drive while impairing the APC anticoagulant response.