rs121918475 — PROS1 Q279X

Pathogenic nonsense variant in protein S that eliminates the anticoagulant cofactor through a premature stop codon, causing autosomal dominant hereditary protein S deficiency and a markedly elevated lifetime risk of venous thromboembolism

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PROS1 Q279X — A Stop Codon That Disables the Clotting Brake

Blood clots when you need them to; the rest of the time, a network of natural anticoagulants keeps coagulation in check. Protein S — encoded by the PROS1 gene — is one of those brakes. It acts as a cofactor for activated protein C (APC)11 activated protein C (APC)
APC cleaves and inactivates coagulation Factors Va and VIIIa, shutting down the amplification loop that generates thrombin, the enzyme that forms blood clots. Without sufficient protein S, APC cannot do its job efficiently, and coagulation goes unrestrained. rs121918475 — known as the Q279X or p.Gln279Ter variant — introduces a premature stop codon22 premature stop codon
CAG (glutamine) is changed to TAG (stop) at amino acid position 279 of the canonical PROS1 isoform; position 311 in the longer isoform at a site well before the protein's functional C-terminus, producing a severely truncated, non-functional protein. This is a pathogenic, well-characterized cause of hereditary protein S deficiency.

The Mechanism

PROS1 encodes a 676-amino-acid vitamin K–dependent plasma glycoprotein. The Q279X variant truncates the protein at position 279, eliminating the two Laminin G-like domains33 Laminin G-like domains
Laminin G domains mediate the interaction between protein S and APC, as well as protein S's direct role in inhibiting Factor Xa and Factor Va independently of APC in the C-terminus that are essential for APC cofactor activity. The truncated product — if it is even stably expressed — retains no meaningful anticoagulant function.

Because Q279X is a stop-gain variant, the truncated transcript also undergoes nonsense-mediated mRNA decay (NMD)44 nonsense-mediated mRNA decay (NMD)
A cellular surveillance mechanism that degrades mRNA molecules with premature stop codons to prevent synthesis of aberrant proteins in most mammalian cells, meaning protein S output from the affected allele may be near zero. The result in heterozygotes is typically a Type I protein S deficiency: plasma levels of total protein S antigen, free protein S antigen, and protein S activity are all reduced to roughly 40–60% of normal — consistent with the population-level measurement of 48% of normal in high-risk PROS1 variant carriers from the 2025 UK Biobank study55 2025 UK Biobank study
Chaudhry et al. measured total protein S levels in carriers of high-risk PROS1 variants (functional impact score = 1.0) across 426,436 UK Biobank participants.

The Evidence

This variant has the highest tier of clinical evidence: it is classified Pathogenic in ClinVar (OMIM 176880.0007), it has been confirmed through direct PROS1 mutational screening in affected families, and it is curated by the OMIM-Curated Records review panel. The Q279X change has been documented in multiple independent families and confirmed by haplotype analysis66 haplotype analysis
Hurtado et al. showed that Q279X arises on more than one haplotype background, indicating it has occurred as a recurrent de novo mutation rather than descending from a single founder, establishing it as a recurrent pathogenic variant rather than a population-specific founder mutation.

At the population scale, a 2025 JAMA study of 630,000 biobank participants77 2025 JAMA study of 630,000 biobank participants
Chaudhry, Haj, Ryu et al., published April 2025 in JAMA, combining UK Biobank (426,436) and All of Us (204,006) cohorts found that carriers of high-risk PROS1 variants — loss-of-function alleles with a functional impact score of 1.0, in the same tier as Q279X — face an adjusted odds ratio of 14.01 (95% CI 6.98–27.14, P = 9.09 × 10⁻¹¹) for venous thromboembolism, making it one of the strongest single-gene thrombophilia risk factors quantified in unselected population cohorts.

For pregnancy specifically88 pregnancy specifically
Croles et al. 2017 meta-analysis of 36 observational studies covering all major thrombophilias during pregnancy, protein S deficiency raises the absolute postpartum VTE risk to 4.2% (95% CrI 0.7–9.4%). In women using combined oral contraceptives99 women using combined oral contraceptives
Van Vlijmen et al. 2016 systematic review and meta-analysis; "severe" thrombophilias defined as antithrombin, protein C, or protein S deficiency, VTE risk rises to an absolute rate of 4.3–4.6 per 100 pill-years — a level at which guidelines uniformly recommend against combined hormonal contraceptive use.

The 2023 American Society of Hematology guidelines on thrombophilia testing1010 thrombophilia testing
Middeldorp et al., Blood Advances 2023 conditionally recommend testing first-degree relatives of known protein S deficiency carriers before starting combined hormonal contraceptives or other thrombosis-promoting therapies, and before pregnancy.

Practical Implications

A Q279X carrier faces three categories of actionable risk. First, protein S levels should be confirmed by laboratory testing — plasma total and free protein S antigen plus protein S activity — both to quantify the deficiency and to document it for medical providers. Second, situations that further activate the coagulation system (combined hormonal contraceptives, surgery, immobility, pregnancy, postpartum period) carry acutely elevated thrombosis risk that is quantifiable and in most cases preventable with appropriate prophylaxis. Third, thrombosis events themselves may require longer anticoagulation than in non-carriers, since the underlying coagulation imbalance persists after an acute event.

For anticoagulation after a VTE event, full-dose DOACs (rivaroxaban, apixaban)1111 full-dose DOACs (rivaroxaban, apixaban)
Kovac et al. 2024 ISTH SSC communication; hazard ratios for recurrent VTE on full-dose DOACs ranged from 0.3 to 0.75 in cohort studies; low-dose DOACs were not assessed in severe thrombophilia and should be avoided appear comparable to warfarin in severe thrombophilia, with caution against reduced-dose ("half-tablet") regimens due to insufficient evidence.

Interactions

The most clinically important interaction is with Factor V Leiden (rs6025, F5 R506Q)1212 Factor V Leiden (rs6025, F5 R506Q)
Factor V Leiden is the most common inherited thrombophilia (~5% of Europeans); it creates a coagulation Factor Va molecule resistant to cleavage by APC, meaning protein S deficiency and Factor V Leiden attack the same APC-dependent pathway from different sides. A carrier of both Q279X and Factor V Leiden would face a compounded impairment of the APC anticoagulant pathway, with predicted risk exceeding either variant alone. Similarly, the prothrombin G20210A variant (rs1799963)1313 prothrombin G20210A variant (rs1799963)
Raises plasma prothrombin 30%, pushing the coagulation system toward clotting while protein S deficiency simultaneously weakens the brake would be additive with protein S deficiency on the thrombosis side of the ledger.

Acquired thrombophilic states — antiphospholipid syndrome, active malignancy, nephrotic syndrome (which causes urinary loss of protein S), pregnancy, and immobilization — all compound with Q279X in an additive or synergistic manner. Vitamin K antagonists (warfarin) paradoxically reduce protein S levels as part of their mechanism of action; this is relevant when initiating anticoagulation or managing a carrier who is perioperatively bridged.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

Normal PROS1 gene — no protein S deficiency from this variant

You carry two copies of the common G allele at rs121918475. Your PROS1 gene does not carry the Q279X premature stop codon and produces functional protein S normally. This genotype is found in virtually all individuals — the Q279X variant is exceedingly rare, with an allele frequency of approximately 0.000002 in gnomAD exomes (1 in 594,322 alleles tested). You do not have hereditary protein S deficiency from this variant.

AG Q279X Carrier High Risk

One copy of PROS1 Q279X — hereditary protein S deficiency (Type I) with markedly elevated VTE risk

Protein S deficiency caused by Q279X is classified as Type I: all three measurable protein S parameters are reduced in proportion — total antigen, free antigen, and activity. This distinguishes it from Type II deficiency (normal antigen, reduced activity) and Type III (normal total, reduced free antigen). Type I caused by a truncating mutation is among the most clearly pathogenic protein S deficiency subtypes.

Key risk windows:

Combined oral contraceptives: Estrogen increases production of coagulation factors and reduces protein S levels further, compounding an already reduced anticoagulant reserve. The absolute VTE rate in severe hereditary thrombophilia carriers on combined hormonal contraceptives reaches 4.3–4.6 per 100 pill-years — levels at which guidelines uniformly recommend against combined hormonal methods.

Pregnancy and postpartum: Pregnancy further suppresses protein S (a physiological change that normally reduces to ~40% during pregnancy), making Q279X carriers doubly deficient. The postpartum window (particularly the first 6 weeks) carries the highest absolute VTE risk: ~4% for protein S deficiency carriers vs. ~0.1% in the general postpartum population.

Surgery and immobility: Any period of reduced venous blood flow (prolonged immobility, surgery) removes the mechanical contribution to clot prevention, leaving the biochemical brake (protein S) as the primary restraint — and that brake is already at half capacity.

Anticoagulation duration: After a first VTE, the decision about treatment duration (3–6 months vs. extended/indefinite) should account for Q279X carrier status; hematology consultation is warranted.

AA Q279X Homozygous High Risk

Two copies of PROS1 Q279X — severe hereditary protein S deficiency with very high thrombosis risk from birth

Homozygous protein S deficiency due to two null alleles presents with near- complete absence of plasma protein S. The clinical consequences are severe and begin at birth: neonatal purpura fulminans — widespread skin necrosis from microvascular thrombosis — is the hallmark presentation in newborns who are homozygous for null PROS1 variants. In milder homozygous cases where some residual activity exists, recurrent DVT and PE typically begin in childhood or early adulthood without anticoagulant treatment.

Management of homozygous protein S deficiency requires long-term or lifelong anticoagulation. In historical case series, fresh-frozen plasma or protein S concentrate infusions were used acutely; long-term management has evolved toward indefinite anticoagulation with warfarin or DOACs (with specialist guidance), and in some centers liver transplantation has been used to cure the underlying deficiency.

All first-degree relatives of both parents of a homozygous individual are obligate heterozygotes for Q279X.