rs387906674 — PROS1 R355C

Rare pathogenic missense variant in protein S causing hereditary type III protein S deficiency, with carriers at elevated risk for venous thromboembolism and white matter stroke

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PROS1 R355C — Protein S Deficiency and the Risk of Silent Stroke

Protein S, encoded by the PROS1 gene on chromosome 3, is a vitamin K-dependent11 vitamin K-dependent
Protein S requires vitamin K for gamma-carboxylation of its Gla domain — a post-translational modification essential for membrane binding and anticoagulant function plasma glycoprotein that acts as a cofactor for activated protein C (APC) and tissue factor pathway inhibitor (TFPI). Together these brake the coagulation cascade — specifically disabling factors Va and VIIIa. When protein S is deficient, these brakes fail, and the blood is biased toward clotting. The R355C variant (rs387906674) causes hereditary protein S deficiency and was first linked to an unusually severe stroke phenotype in a three-generation Chinese family22 three-generation Chinese family
Six of eleven family members carried the mutation; all adult carriers showed white matter infarctions on MRI, while none of the noncarriers did.

The Mechanism

The PROS1 gene sits on the minus strand of chromosome 3 and encodes a 676-amino-acid mature protein with distinct structural domains: an N-terminal Gla domain, a thrombin-sensitive region, four EGF-like repeats, and a C-terminal sex hormone binding globulin (SHBG)-like region composed of two laminin G-like domains (LG1 and LG2). Arginine 355 sits in the LG1 domain — the very region that mediates TFPI cofactor activity and is competitively regulated by C4b-binding protein (C4BP). The LG1 domain contains critical residues for TFPI-alpha interaction33 LG1 domain contains critical residues for TFPI-alpha interaction
Protein S LG1 is required for TFPI cofactor function; C4BP binding to LG1 almost completely abolishes this activity — a competitive mechanism that reduces functional free protein S.

The substitution of arginine (positively charged, large) for cysteine (small, can form aberrant disulfide bonds) at position 355 disrupts the local fold of LG1. Laboratory studies in affected carriers showed protein S deficiency type III44 protein S deficiency type III
Type III: total protein S normal, but free protein S and functional activity are reduced — the most diagnostically challenging subtype because a standard total protein S test will appear normal: total plasma protein S levels are normal, but free protein S levels and APC-cofactor activity are reduced. This reflects impaired secretion or altered C4BP binding rather than reduced gene transcription.

The Evidence

The R355C variant was first reported by Leung et al. in Neurology (2010)55 Leung et al. in Neurology (2010)
Leung TW et al. Genetic predisposition of white matter infarction with protein S deficiency and R355C mutation. Neurology. 2010;75(24):2156–63 in a Chinese family where haplotype analysis mapped the defect to a 6.1-Mb region on chromosome 3q11.2 (lod = 3.0). All adult R355C carriers showed deep white matter infarctions in borderzone regions on MRI — territory supplied by the distal ends of penetrating arteries and particularly vulnerable to hypoperfusion or microembolic occlusion. Strikingly, none of ten additional protein S deficiency families lacking this specific mutation showed cerebral infarction, raising the possibility that R355C impairs protein S function in the cerebral vasculature through a mechanism beyond simple quantitative deficiency.

In the broader context of PROS1 pathogenic variants, Ten Kate et al. in Human Mutation (2008)66 Ten Kate et al. in Human Mutation (2008)
Analysis of 87 pedigrees across two phenotypic types found that type I protein S deficiency (low total and free PS) is overwhelmingly monogenic — PROS1 mutations identified in 34 of 35 probands — while type III (normal total, low free PS) is genetically heterogeneous. However, Castoldi et al. in Haematologica (2010)77 Castoldi et al. in Haematologica (2010)
242 individuals from 30 families, 132 genetically characterized demonstrated that type I and type III deficiencies confer similar hypercoagulable states and equivalent thrombosis-free survival when assessed together in mixed-type families, arguing against dismissing type III as low-risk.

Among Chinese VTE patients, Wu et al. (2022)88 Wu et al. (2022)
603 VTE patients and 584 matched controls; Frontiers in Cardiovascular Medicine quantified an odds ratio of 8.1 (95% CI 3.6–19.9) for VTE in individuals with protein S deficiency, with 43% of PROS1 coding-variant carriers experiencing VTE in their lifetime.

The variant is extremely rare globally — gnomAD v4 identifies only 6 alternate alleles across 1.4 million chromosomes sampled, with the highest frequency in East Asian populations (~0.008%). No homozygotes have been reported in population databases.

Practical Implications

Carriers of R355C should pursue functional free protein S assay99 functional free protein S assay
Total protein S ELISA will appear normal in type III deficiency — only the free fraction and activity assays reveal the defect; testing ideally deferred 4+ weeks after an acute thrombotic event or VKA therapy testing to confirm the phenotype and establish a baseline. Because total protein S levels are normal, this deficiency is frequently missed on routine coagulation panels.

Oral contraceptives containing estrogen independently reduce protein S levels by 20–30% through effects on hepatic synthesis, potentially unmasking or compounding the existing deficiency in heterozygous carriers. Pregnancy produces a physiological drop in free protein S that is already hazardous in protein S-deficient women. Anticoagulation decisions following a thrombotic event should account for the additional hereditary component: most guidelines recommend extended anticoagulation (beyond 3 months) after an unprovoked VTE in carriers of high-risk thrombophilia variants.

Interactions

The most important interactions are with other inherited thrombophilias. Compound heterozygosity with Factor V Leiden (rs6025, FV R506Q)1010 Factor V Leiden (rs6025, FV R506Q)
The most common inherited thrombophilia in Europeans, present in 5%; double heterozygosity with any high-risk thrombophilia dramatically compounds VTE risk or with the prothrombin G20210A variant (rs1799963, F2)1111 prothrombin G20210A variant (rs1799963, F2)
G20210A raises prothrombin levels 30% and is found in 1–3% of Europeans; both variants impair anticoagulation through independent mechanisms would place a carrier at very high thrombotic risk. Acquired protein S reductions — from liver disease, antiphospholipid syndrome, nephrotic syndrome, or inflammatory states — further lower the functional protein S baseline already reduced by R355C.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

Normal protein S gene at this position — no R355C protein S deficiency

You carry two copies of the common G allele at rs387906674, meaning your PROS1 gene at this position is unchanged from the reference sequence. You do not carry the R355C pathogenic variant associated with hereditary protein S deficiency type III. This is the nearly universal genotype — the alternate A allele is detected in fewer than 1 in 10,000 chromosomes globally.

AG R355C Carrier Carrier

One copy of PROS1 R355C — hereditary protein S deficiency type III, elevated thrombosis and stroke risk

Protein S deficiency type III caused by R355C is particularly important because the diagnosis is routinely missed on standard coagulation panels: total protein S levels appear normal, and only a free protein S activity assay will reveal the reduction. Establishing a confirmed laboratory phenotype is an essential first step for carriers.

The R355C substitution disrupts the first laminin G-like domain (LG1) of protein S, impairing its function as a cofactor for tissue factor pathway inhibitor (TFPI) — a separate anticoagulant role from its better-known activated protein C (APC) cofactor activity. The LG1 domain is also the site of C4b-binding protein (C4BP) interaction; altered C4BP binding may shift the balance toward the bound (non-functional) pool of protein S, which explains why free protein S activity falls while total antigen remains near normal.

Approximately 50% of heterozygous carriers of pathogenic PROS1 mutations will experience a venous thrombotic event during their lifetime. Key provocation-specific risks:

  • Estrogen-containing contraceptives: Oral contraceptives reduce protein S by 20–30% through hepatic effects, potentially compounding the existing deficiency and markedly increasing VTE risk.
  • Pregnancy and postpartum: Physiological protein S reduction in pregnancy reaches its nadir in the third trimester and remains low postpartum — the period of highest absolute thrombotic risk.
  • Surgery and immobilization: Standard surgical thromboprophylaxis applies, but carrier status should be documented so that extended prophylaxis can be considered.
  • Warfarin initiation: Starting warfarin without initial heparin cover can cause warfarin-induced skin necrosis in protein S-deficient patients — always bridge with a rapidly acting anticoagulant first.
AA R355C Homozygous Homozygous

Two copies of PROS1 R355C — homozygous protein S deficiency, very high thrombosis risk

Homozygous PROS1 loss-of-function represents a near-complete absence of functional protein S. The anticoagulant pathway mediated by protein S (APC cofactor activity and TFPI cofactor activity) would be profoundly impaired. Although no homozygous R355C individual has been reported, extrapolating from other homozygous PROS1 pathogenic mutations indicates:

  • Neonatal purpura fulminans or severe VTE in early childhood in fully null mutations
  • Very early onset thrombosis in partial-function homozygotes
  • Possible need for long-term anticoagulation from diagnosis

If this result is confirmed on a repeat sample using a second method (sequencing artifacts can produce false apparent homozygosity), urgent hematology referral is required before any clinical decision is made.