rs121909567 — SERPINC1 Budapest 3 (Leu131Phe)

Pathogenic missense in antithrombin III; the A allele causes type II heparin-binding-site (HBS) antithrombin deficiency with heterozygotes carrying 3-5x VTE risk and homozygotes facing severe, often childhood-onset thrombophilia

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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.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

Normal antithrombin III function — no Budapest 3 variant detected

You carry two copies of the common G allele at rs121909567, meaning your SERPINC1 gene produces fully functional antithrombin III with an intact heparin-binding site. This is the universal common genotype worldwide; the pathogenic A allele is extremely rare globally (frequency approximately 0.002% in European populations). You do not carry the Budapest 3 (Leu131Phe) antithrombin deficiency variant.

AA Homozygous Budapest 3 High Risk

Two copies of Budapest 3 — severe antithrombin deficiency requiring specialist management from early life

Homozygous Budapest 3 carries three clinically critical complications that distinguish it from heterozygous AT deficiency and require specialized management:

Heparin resistance: Standard heparin anticoagulation relies on AT-III as its molecular intermediary. With near-absent functional AT-III, heparin cannot achieve adequate anticoagulation through its normal mechanism. During acute VTE treatment, surgery, or labor, antithrombin concentrate infusion is typically required before or alongside heparin to restore sensitivity. Providers unaware of the diagnosis may escalate heparin to dangerous doses before recognizing the resistance.

IVC system atresia: A 2021 multicentre study found that 70.8% of homozygous Budapest 3 carriers examined by imaging had structural atresia of the inferior vena cava system — believed to result from intrauterine thrombosis during fetal vascular development. This structural anomaly itself predisposes to lower-extremity DVT independent of the biochemical defect.

Pregnancy: Untreated pregnancies in homozygous women have extremely poor outcomes (100% adverse in one case series of 8 women). Even with antithrombin concentrate and LMWH, prematurity is nearly universal and outcomes require intensive specialist coordination. Pre-conception counseling and multidisciplinary planning are essential.

Direct oral anticoagulants (apixaban, rivaroxaban, dabigatran) act upstream of AT-III and may be effective in homozygous carriers who are heparin-resistant; this requires specialist guidance and emerging evidence supports their use in some clinical scenarios.

AG AT Budapest 3 Carrier Carrier

One copy of Budapest 3 — partial antithrombin III deficiency with significantly elevated VTE risk

Type II HBS antithrombin deficiency is clinically distinct from type I deficiency (where AT-III protein quantity is reduced). In type II HBS, functional anti-Xa and anti-IIa assays detect the defect because the protein is present but inactive; immunological assays measuring protein mass can appear borderline or normal, which has caused missed diagnoses in some case reports.

Key risk-elevating circumstances for heterozygous carriers: - Combined hormonal contraceptives: Estrogen-containing methods increase VTE risk 3-5 fold in the general population; in AT-deficient carriers this interaction is multiplicative and combined hormonal methods should be strongly avoided. - Pregnancy: Pregnancy physiologically lowers AT-III levels by ~20% in all women; this atop baseline deficiency creates a critical window. LMWH prophylaxis is standard of care in carriers with prior VTE history. - Surgery and prolonged immobility: Perioperative VTE risk is significantly elevated; thromboprophylaxis and surgical disclosure are essential. - Heparin resistance: Because heparin requires AT-III to exert its anticoagulant effect, carriers may show somewhat reduced heparin response, particularly during acute thrombotic episodes or surgery requiring high heparin doses.

First-degree relatives (parents, siblings, children) each have a 50% probability of carrying the same variant and warrant cascade genetic testing, especially women of childbearing age or anyone planning surgery.