rs387906675 — PROS1 Y234C

Pathogenic missense variant in the vitamin K-dependent anticoagulant gene PROS1; homozygotes develop severe neonatal protein S deficiency with life-threatening thrombosis, and heterozygotes carry partial deficiency with meaningfully elevated VTE risk

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PROS1 Y234C — A Rare, High-Magnitude Anticoagulant Gene Variant

Protein S — encoded by the PROS1 gene on chromosome 3q11.1 — is one of the body's primary anticoagulant regulators. It circulates in plasma partly free (the active anticoagulant fraction, ~40%) and partly bound to C4b-binding protein (~60%). Free protein S serves as a cofactor for activated protein C (APC)11 activated protein C (APC)
APC degrades the procoagulant factors Va and VIIIa, acting as a molecular brake on the coagulation cascade, preventing excessive fibrin clot formation. Protein S can also inhibit coagulation independently of protein C by directly blocking prothrombinase and tenase complex assembly. The PROS1 Y234C variant (rs387906675) is one of the rarest and most severe single-nucleotide mutations in this gene: homozygous carriers develop protein S activity below 10%22 protein S activity below 10%
Measured in the index patient from Fischer et al., 2010; normal range is roughly 60–140% of mean reference activity, producing life-threatening neonatal thrombosis.

The Mechanism

The c.701A>G transition (plus-strand notation: T>C at rs387906675) changes tyrosine at position 234 to cysteine in the protein S polypeptide chain. Tyrosine 234 is located within the laminin G-type (LG) domain33 laminin G-type (LG) domain
A structural domain important for protein S binding to C4b-binding protein and factor Xa; point mutations here typically disrupt both secretion and cofactor function of protein S. The introduction of a free thiol group from cysteine in this structurally constrained position disrupts protein folding, likely preventing normal secretion from hepatocytes or degrading the mature protein's ability to bind and activate protein C. The net effect is either absent or non-functional protein S — clinically indistinguishable from a null allele in terms of residual anticoagulant activity.

Heterozygous carriers produce approximately half the normal amount of functional protein S from the intact allele. This partial deficiency (typically 30–60% of normal free protein S activity) is sufficient for most everyday hemostasis but creates a measurable prothrombotic state, especially under provoking circumstances — pregnancy, oral contraceptive use, surgery, prolonged immobility, or intercurrent illness.

The Evidence

The variant was first reported by Fischer and colleagues in 201044 first reported by Fischer and colleagues in 2010
Neonatology 2010, 98(4):337–40; case of an Albanian-origin infant in an infant born of consanguineous parents who presented on day four of life with seizures and hemorrhagic shock. MRI revealed massive intracranial hemorrhage; coagulation studies demonstrated protein S activity below 10%. The infant subsequently developed aortic thrombosis and died on day eight. Post-mortem examination showed diffuse thromboses of intracerebral capillaries, confirming the underlying prothrombotic state produced both thrombotic and hemorrhagic pathology simultaneously — the paradox of severe thrombophilia, where occlusion of small vessels causes ischemic infarction and secondary hemorrhage upstream.

For heterozygous carriers, risk quantification comes from broader protein S deficiency cohort data. A 2025 population-scale JAMA study55 2025 population-scale JAMA study
UK Biobank + NIH All of Us; 600,000+ participants, 18,011 VTE events stratified PROS1 variant risk by mutation class: heterozygous carriers of missense PROS1 variants had OR 1.98 for VTE, while carriers of complete loss-of-function variants (nonsense, frameshift, essential splice site) had OR 14.01. Y234C functionally approximates a loss-of-function allele given residual protein S activity near zero, placing heterozygous carriers toward the higher end of the missense risk spectrum. A Danish family cohort66 Danish family cohort
87 PS-deficient participants and relatives; Christensen et al. 2021 found 43% of individuals with coding PROS1 variants experienced at least one VTE, versus 17% in non-carrier family members. Prospective follow-up data estimate an annual first-VTE incidence of ~0.7% in heterozygous protein S deficiency77 ~0.7% in heterozygous protein S deficiency
Comparable to other high-penetrance inherited thrombophilias such as protein C deficiency and antithrombin deficiency — roughly 5-fold above the population baseline. Recurrence risk after a first event is substantially higher: 6–10% per year88 6–10% per year.

Practical Implications

For heterozygous carriers who have not had a VTE, the priority is identifying and modifying provoking risk factors — especially estrogen-containing hormonal contraceptives, which independently increase VTE risk 3–5-fold and combine multiplicatively with inherited thrombophilias. Carrier status should be documented prominently in the medical record so that prophylaxis can be given during surgery, prolonged hospitalization, and obstetric care. Direct oral anticoagulants (DOACs — apixaban, rivaroxaban) are now preferred over vitamin K antagonists for most VTE treatment episodes; carriers whose VTE was unprovoked or recurrent should discuss whether indefinite anticoagulation is appropriate.

For homozygous carriers or compound heterozygotes (carrying Y234C on one allele and a different pathogenic PROS1 variant on the other), clinical presentation is often in the neonatal period or early infancy with purpura fulminans, multifocal thrombosis, or intracranial hemorrhage. Emergency management includes fresh frozen plasma (FFP) to restore protein S, followed by long-term anticoagulation and consideration of protein S concentrate where available.

Interactions

The most clinically significant interaction is with Factor V Leiden (rs6025, F5 R506Q)99 Factor V Leiden (rs6025, F5 R506Q)
Factor V Leiden renders activated factor V partially resistant to inactivation by activated protein C — since protein S is the cofactor for APC, these two defects are mechanistically synergistic. A documented case of a child with protein S deficiency plus heterozygous Factor V Leiden developed neonatal purpura fulminans despite each defect being individually less severe. Similarly, compound PROS1/PROC mutations (protein S plus protein C deficiency) produce synergistic prothrombotic effects: severe PS deficiency can unmask a pathogenic PROC variant even when protein C activity appears normal by standard testing.

The prothrombin G20210A variant (rs1799963, F2) is the second most common inherited thrombophilia; in combination with protein S deficiency it compounds VTE risk in an additive fashion, justifying a complete thrombophilia panel in any carrier.

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-carrier Normal

Normal PROS1 alleles — standard protein S anticoagulant function

You carry two copies of the common T allele at rs387906675, meaning both copies of your PROS1 gene are intact at this position. Your protein S production and anticoagulant function from this variant are unaffected. The C (risk) allele at this position is extraordinarily rare globally — found in approximately 1 in 60,000 tested alleles in population databases. The vast majority of people who have any VTE risk from protein S deficiency carry a different PROS1 variant, so a normal result here does not rule out other causes.

CC Y234C Homozygous Deficient

Two copies of Y234C — severe protein S deficiency requiring specialist management

The index case of homozygous PROS1 Y234C was described by Fischer and colleagues (2010): a term neonate of consanguineous Albanian parents who presented on day 4 with seizures and hemorrhagic shock. Protein S activity was less than 10%. Despite stabilization, the infant developed aortic thrombosis and died on day 8. Post-mortem findings showed diffuse capillary thrombosis throughout the cerebral vasculature — the thrombotic occlusions caused ischemia and secondary hemorrhagic infarction, explaining the paradoxical combination of prothrombotic and hemorrhagic findings.

Pathophysiology: with near-zero protein S, the activated protein C (APC) anticoagulant pathway cannot function. Coagulation factors Va and VIIIa accumulate unchecked at sites of injury or inflammation, producing explosive, unregulated thrombin generation. This is distinct from the usual acquired or mild-inherited thrombophilia risk — it represents a near-complete failure of one of the central anticoagulant systems.

Management in documented survivors of neonatal-onset severe protein S deficiency typically involves: - Acute phase: fresh frozen plasma (FFP) or protein S concentrate (where available) to restore functional protein S during thrombotic crisis - Transition: unfractionated heparin or LMWH while initiating warfarin or DOAC (with caution — protein S deficiency creates a window of paradoxical warfarin skin necrosis without heparin bridge) - Long-term: indefinite anticoagulation; warfarin historically, with DOACs increasingly preferred for adult patients - Monitoring: regular protein S activity levels, surveillance for recurrent thrombosis, and consideration of protein S concentrate if available for high-risk periods

Any first-degree relatives (parents will both be obligate heterozygotes) should be tested and counseled. Future pregnancies in the family carry recurrence risk of homozygosity.

CT Y234C Carrier Carrier

One copy of Y234C — partial protein S deficiency with elevated VTE risk

Protein S (PROS1) is a vitamin K-dependent plasma protein that functions as the essential cofactor for activated protein C (APC) in the degradation of coagulation factors Va and VIIIa. When protein S activity falls to the 30–60% range typical of heterozygous pathogenic PROS1 variants, the anticoagulant brake on the clotting cascade is weakened — not eliminated, but meaningfully impaired under conditions that additionally stress the system.

Key risk amplifiers for heterozygous Y234C carriers: - Estrogen-containing contraceptives: Oral contraceptive pills, patches, and vaginal rings containing estrogen reduce protein S levels by 30–50% further, compounding the inherited partial deficiency and increasing VTE risk multiplicatively (estimated 6–15-fold above non-carrier, non-OC baseline). - Pregnancy and the postpartum period: Protein S naturally falls during pregnancy (physiologically); a heterozygous carrier's already-reduced protein S drops further, producing the highest-risk period. VTE risk in pregnancy with protein S deficiency is estimated at 0.5–6% per pregnancy depending on personal and family history. - Surgery and immobility: Standard high-risk thrombotic periods; pharmacological prophylaxis should be considered, particularly for major surgery or inpatient hospitalization. - Combined inherited thrombophilias: Coexisting Factor V Leiden (rs6025) or prothrombin G20210A (rs1799963) dramatically amplifies risk.

After a first VTE event, annual recurrence risk is 6–10% in protein S deficiency, substantially higher than the general post-VTE recurrence risk (~3–5%). This influences the decision about duration of anticoagulation after any VTE episode.