rs121909567 — SERPINC1 Budapest 3 (Leu131Phe)

Antithrombin Budapest 3 — When the Clotting Brake Fails

Your blood's coagulation system is a carefully balanced pair of accelerators and brakes. Antithrombin III (AT-III), encoded by SERPINC1, is one of the most powerful brakes in the system — a natural anticoagulant that continuously inhibits thrombin and other activated clotting factors, preventing runaway clot formation. When a leucine at position 131 of the AT-III protein is replaced by phenylalanine — the Budapest 3 mutation — the protein's heparin-binding site is disrupted, dramatically impairing its ability to function. People who carry one copy of this variant have partial AT-III deficiency; those who carry two copies face severe, lifelong thrombophilia that can manifest in childhood.

The Mechanism

The SERPINC1 gene sits on the minus strand of chromosome 1q25.1. The c.391C>T change (NM_000488.4 notation, minus strand) creates the p.Leu131Phe substitution in the mature protein. This leucine residue sits within the [heparin-binding domain | AT-III has two functional regions: an N-terminal heparin-binding site that dramatically accelerates its inhibitory activity, and a C-terminal reactive site loop that directly inactivates thrombin and Factor Xa] at the protein's N-terminus. Replacing the smaller, aliphatic leucine with the bulkier, aromatic phenylalanine side chain disrupts the local electrostatic environment required for heparin to engage the binding site. Without efficient heparin binding, AT-III's inhibitory rate toward thrombin and Factor Xa falls sharply — published studies confirm reduced heparin affinity and inhibitory activity, as well as impaired structural stability¹¹ reduced heparin affinity and inhibitory activity, as well as impaired structural stability
ClinVar functional evidence summary for VCV000018034; REVEL computational score 0.853 consistent with pathogenicity.

This produces a type II heparin-binding-site (HBS) antithrombin deficiency — the protein is present in near-normal amounts but functions poorly. Functional AT-III assays using anti-Xa activity detect the deficiency reliably; immunological assays that measure AT-III protein quantity can be falsely normal.

The Evidence

The Budapest 3 variant was identified as a founder mutation within Roma (Romani) populations of Central and Eastern Europe, estimated to have originated in the 17th century. A large phenotype study of 102 carriers across 63 Hungarian families²² large phenotype study of 102 carriers across 63 Hungarian families
Gindele et al. Journal of Thrombosis and Haemostasis 2016 found that approximately 54% of heterozygotes experienced venous thrombosis or arterial events. A population study in Hungarian Roma³³ population study in Hungarian Roma
Bereczky et al. Frontiers in Cardiovascular Medicine 2021 found the mutation in approximately 3% of that population and documented VTE in 93% of homozygotes and 44% of heterozygotes surveyed.

Homozygous carriers carry an exceptional burden. A multicentre imaging study of 24 homozygous patients⁴⁴ multicentre imaging study of 24 homozygous patients
de la Morena-Barrio et al. American Journal of Hematology 2021 found that 70.8% had structural atresia of the inferior vena cava system — a rare vascular malformation believed to result from intrauterine thrombosis during fetal development. First VTE events occur in childhood or early adolescence in many homozygotes. In one Turkish case series, sibling deaths at 4 months of age and maternal third-trimester fetal losses were documented⁵⁵ sibling deaths at 4 months of age and maternal third-trimester fetal losses were documented
Sarper et al. J Pediatr Hematol Oncol 2014 within carrier families.

Pregnancy in homozygous women is extremely high risk: a study of 22 pregnancies in 8 homozygous women found a 68% pregnancy loss rate⁶⁶ 68% pregnancy loss rate
Kraft et al. Annals of Hematology 2017, with all untreated pregnancies ending adversely. Successful management of homozygous pregnancy has been reported with combined LMWH plus antithrombin concentrate therapy monitored by thrombin generation assay.

Because AT-III is the primary target of heparin's anticoagulant action, homozygous carriers with near-absent functional AT-III can be [effectively heparin-resistant | Heparin works by binding and activating AT-III; without functional AT-III, heparin cannot exert its anticoagulant effect adequately], a clinically critical complication during surgery, acute VTE management, and labor. The 2025 expert management paper⁷⁷ 2025 expert management paper
Bravo-Pérez et al. J Thromb Haemost 2025 specifically addresses heparin resistance and vena cava anomalies as key complications requiring specialist experience.

The variant is classified Pathogenic by the ClinGen Thrombosis Variant Curation Expert Panel⁸⁸ ClinGen Thrombosis Variant Curation Expert Panel
Expert panel review confers the highest ClinVar review status (4 stars); reviewed September 2023 based on strong segregation data (PP1 strong), pathogenic computational evidence (PP3), and very strong case enrichment (PS4 very strong).

Practical Implications

Heterozygous carriers should be managed as carriers of a moderate-to-high-risk thrombophilia: anticoagulation disclosure before surgery or immobilization, avoidance of combined hormonal contraceptives, and LMWH prophylaxis during pregnancy. Homozygous carriers require hematology specialist management as a matter of urgency — the severity of this genotype is comparable to the most serious inherited thrombophilias, and standard heparin therapy may be insufficient during acute events without antithrombin concentrate supplementation.

Functional AT-III assays (anti-Xa based) are the appropriate diagnostic test; immunological assays that measure protein quantity rather than activity can appear normal in type II HBS deficiency and will miss this diagnosis.

Interactions

The thrombotic risk from Budapest 3 is amplified by all common secondary thrombophilic states. Compound heterozygosity with [Factor V Leiden (rs6025, F5 R506Q) | The most common inherited thrombophilia in Europeans, present in ~5%] or [Factor II G20210A (rs1799963) | Second most common; raises prothrombin levels 30%] would markedly increase VTE risk beyond that of AT deficiency alone — the combination of a defective brake and an overactive accelerator creates severe thrombophilic phenotype. Acquired AT-III consumption states — disseminated intravascular coagulation (DIC), nephrotic syndrome, liver disease, L-asparaginase chemotherapy — can reduce residual AT-III activity further in carriers, potentially precipitating acute thrombosis. Heparin therapy itself moderately reduces circulating AT-III; in homozygous carriers this matters greatly and may necessitate AT concentrate supplementation during heparin treatment.