rs121918474 — PROS1 K196E (Lys196Glu)

PROS1 K196E — Protein S Deficiency and Venous Clotting Risk

When a blood vessel is damaged, the body must rapidly form a clot—but equally important is knowing when to stop. Protein S¹¹ Protein S
Protein S is a vitamin K-dependent anticoagulant glycoprotein synthesized primarily in the liver, endothelial cells, and megakaryocytes. It circulates both free (active, ~40%) and bound to C4b-binding protein (~60%). Only free protein S functions as an anticoagulant cofactor. is one of the body's key brakes on coagulation: it acts as an essential cofactor for activated protein C (APC)²² activated protein C (APC)
Activated protein C is a serine protease that degrades clotting factors Va and VIIIa, the two amplifiers of the coagulation cascade. Without protein S as its cofactor, APC's anticoagulant activity is severely impaired, allowing the clotting cascade to continue unchecked., facilitating the degradation of clotting factors Va and VIIIa. When protein S is reduced, the coagulation brake weakens—and blood clots can form in veins where they don't belong.

The PROS1 K196E variant (c.586A>G, NM_000313.4) is a pathogenic missense mutation replacing a positively charged lysine with a negatively charged glutamic acid at position 196 of protein S. Classified as Pathogenic in ClinVar (variation ID 13318)³³ ClinVar (variation ID 13318)
Review status: criteria provided, multiple submitters, no conflicts — a 2-star review status indicating independent clinical classification agreement for both autosomal dominant and autosomal recessive thrombophilia, and listed as OMIM allelic variant 176880.0003⁴⁴ OMIM allelic variant 176880.0003
OMIM: Online Mendelian Inheritance in Man. 176880 is the PROS1 gene entry; .0003 denotes the third catalogued pathogenic allelic variant in this gene. The variant is rare globally but notably enriched in East Asian populations — the TOMMO Japanese cohort (N=77,444) identifies the C allele at approximately 1% frequency, compared to effectively absent in European and African populations.

The Mechanism

The K196E substitution falls within the sex hormone-binding globulin (SHBG)-like domain⁵⁵ sex hormone-binding globulin (SHBG)-like domain
The SHBG-like domain (also called the laminin G-type domain) of protein S mediates its direct anticoagulant activities independent of activated protein C — including direct inhibition of factors Xa and Va and enhancement of tissue factor pathway inhibitor (TFPI) activity on the cell surface of protein S. Replacing Lys196 with Glu introduces a charge reversal in a region critical for both protein-protein interactions and for the conformational integrity of the SHBG-like domain. The functional consequence is reduced free protein S activity — heterozygous carriers typically have free protein S levels in the 40–60% of normal range (type I deficiency pattern: concordantly reduced antigen and activity).

Research from Fenclova et al., 2023⁶⁶ Fenclova et al., 2023
Fenclova T et al. Res Pract Thromb Haemost 2023;7(4):100110 — 76 patients with suspected protein S deficiency, 17 missense mutations analyzed. SHBG-region mutations showed OR 5.17 (95% CI 1.29–20.65) for thrombosis vs non-SHBG mutations, p=0.02. found that PROS1 missense mutations in the SHBG-like domain carried an independently elevated thrombotic risk compared to mutations elsewhere in the protein—suggesting the location of K196E within this domain may compound the functional impact beyond simply lowering protein S levels.

The Evidence

The most definitive population-scale data comes from Chaudhry et al., JAMA, 2025⁷⁷ Chaudhry et al., JAMA, 2025
Chaudhry SA et al. JAMA 2025;333(16):1423–1432 — N=426,436 UK Biobank participants (44,431 with plasma proteomics), N=204,006 NIH All of Us participants; 18,011 VTE cases. This study stratified PROS1 variants by functional impact score (FIS). High-impact variants (nonsense, frameshift, essential splice sites, FIS=1.0) conferred an OR of 14.01 (95% CI 6.98–27.14) for venous thromboembolism — the strongest genetic thrombosis risk estimated in a population cohort. PROS1 missense variants with FIS ≥0.7 conferred an OR of 1.977 (95% CI 1.552–2.483, p=1.95×10⁻⁷). The K196E variant's specific FIS and VTE risk in this study were not individually reported, but as a pathogenic missense variant classified by multiple clinical laboratories, it falls within the high-impact category.

Importantly, the study found no association between PROS1 variants and arterial thrombosis (myocardial infarction, peripheral artery disease, stroke), confirming protein S deficiency as a specifically venous thrombotic risk.

Lifetime risk elevation is sustained: Kaplan-Meier analysis showed VTE risk remained elevated throughout adult life for PROS1 high-impact variant carriers (log-rank p=0.0005).

Practical Actions

For K196E carriers, the core clinical actions are: confirm biochemical protein S levels, assess cumulative VTE risk given personal history and circumstances, and strategically deploy anticoagulation during high-risk periods. Protein S deficiency is particularly important to recognize before situations that independently elevate clotting risk — surgery, prolonged immobilization, pregnancy, and estrogen-containing contraceptives.

Venous thromboembolism from protein S deficiency typically presents as deep vein thrombosis (DVT) of the lower limbs or pulmonary embolism (PE), but unusual sites such as portal, mesenteric, or cerebral vein thrombosis have been documented in PROS1 variant carriers. A first unprovoked DVT or PE in a person with K196E should prompt specialist hematology evaluation and decisions about duration of anticoagulation.

Note that protein S levels fluctuate physiologically — they fall during pregnancy, with oral contraceptives, and during acute illness or warfarin therapy. Testing must be performed in the correct clinical context to avoid misinterpretation. Genetic confirmation of K196E is the most reliable long-term identifier of protein S deficiency.

Interactions

K196E acts within the broader natural anticoagulant system, which includes protein C (encoded by PROC) and antithrombin (encoded by SERPINC1). Concurrent genetic defects in two anticoagulant pathways dramatically amplify thrombotic risk — a PROS1 K196E carrier who also carries a pathogenic PROC or SERPINC1 variant, or who is heterozygous for Factor V Leiden (rs6025), faces substantially higher lifetime VTE risk than any single deficiency alone. Factor V Leiden is common (~3–8% of Europeans) and synergizes with natural anticoagulant deficiencies. Genetic testing panels that include PROC, SERPINC1, F2 prothrombin (rs1799963), and Factor V Leiden should be considered in K196E carriers.