rs121909569 — SERPINC1 Ser148Pro

Likely pathogenic missense variant in antithrombin III; the G allele converts Ser148 to Pro, causing type II pleiotropic antithrombin deficiency that reduces both anticoagulant activity and antigen levels, substantially elevating lifetime VTE risk in heterozygous carriers

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SERPINC1 Ser148Pro — Antithrombin's Gatekeeper Compromised

Antithrombin — encoded by SERPINC1 on chromosome 1 — is the principal brake on coagulation. It is a serpin11 serpin
serine protease inhibitor: a family of proteins that regulate coagulation, fibrinolysis, and inflammation by acting as decoy substrates for serine proteases that permanently inactivates thrombin and Factor Xa, the two enzymes most responsible for generating fibrin clot. Without functional antithrombin, coagulation runs unchecked at the slightest provocation. The Ser148Pro variant (rs121909569) in SERPINC1 substitutes proline for serine at position 148, altering the protein's conformation in a way that impairs both its heparin-binding capacity and its reactive site — a dual defect that defines type II pleiotropic effect (type II-PE) antithrombin deficiency22 type II pleiotropic effect (type II-PE) antithrombin deficiency
The most clinically severe subtype: type I reduces antigen and activity equally; type II-HBS reduces heparin binding only; type II-PE reduces both heparin-dependent and heparin-independent anticoagulant activity.

The Mechanism

Antithrombin inhibits its target proteases through a conformational mechanism called the serpin suicide substrate pathway. The reactive site loop — the region that presents itself as a decoy peptide to thrombin and Factor Xa — must be positioned correctly, and heparin binding dramatically accelerates the inhibitory reaction by bridging antithrombin to its targets. The Ser148Pro substitution introduces a proline residue into a region of the protein that connects the heparin-binding domain to the reactive site loop. Proline is conformationally rigid — it eliminates a peptide bond rotational degree of freedom that other amino acids allow — and its insertion at position 148 disrupts the transmission of the conformational change that heparin binding normally induces. The result is impaired heparin-dependent acceleration AND reduced baseline reactive site efficiency33 impaired heparin-dependent acceleration AND reduced baseline reactive site efficiency
Pleiotropic effect classification: affects both the heparin-binding arm and the reactive site — the two mechanisms by which antithrombin inactivates thrombin and Factor Xa. Plasma antithrombin activity and antigen levels typically fall to 40–60% of normal in heterozygous carriers, leaving half the normal coagulation brake.

Homozygous antithrombin deficiency has not been reported in viable offspring, suggesting complete absence of antithrombin activity is incompatible with survival — underscoring how essential this protein is to basic hemostasis.

The Evidence

A 2024 systematic review and meta-analysis by Alnor et al.44 2024 systematic review and meta-analysis by Alnor et al.
39167180: Anne Alnor, Annals of Hematology — pooled data across multiple cohort studies of hereditary thrombophilia placed antithrombin deficiency at an odds ratio of 4.01 (95% CI 2.50–6.44) for venous thromboembolism — intermediate between homozygous Factor V Leiden (OR 5.58) and heterozygous Factor V Leiden (OR 2.97). This positions AT deficiency as a high-impact inherited thrombophilia, albeit with wide confidence intervals reflecting the rarity of prospective cohort data.

A review of hereditary antithrombin deficiency treatment55 review of hereditary antithrombin deficiency treatment
Rodgers GM, Thromb Haemost 2009 synthesized earlier cohort data and estimated a ≥50% lifetime risk of VTE in confirmed AT-deficient individuals — three to seven times higher than the residual risk associated with other thrombophilias such as protein C or protein S deficiency. Antithrombin levels in heterozygous carriers typically run at 40–60% of normal — an unusually severe haploinsufficiency for a dominant variant.

The pregnancy-specific risk is particularly elevated66 particularly elevated
Croles et al. BMJ 2017 Bayesian meta-analysis; RCT-level data are unavailable for ethical reasons, so Bayesian modeling of observational studies provides the best evidence: antithrombin deficiency carries an estimated 7.3% antepartum VTE risk (95% credible interval 1.8–15.6%) and 11.1% postpartum risk (3.7–21.0%). These absolute risks are among the highest of any inherited thrombophilia and drive the ACOG and ACCP recommendations for anticoagulant prophylaxis in affected pregnant women.

In a population-based cohort of 29,387 middle-aged Swedish adults77 population-based cohort of 29,387 middle-aged Swedish adults
Manderstedt et al. JAHA 2022; Malmö Diet and Cancer cohort followed from 1991–2018, SERPINC1 disease-causing mutation carriers had a hazard ratio of 1.6 (95% CI 1.3–1.9) for incident VTE. This real-world unselected population estimate is lower than estimates from thrombophilia clinic cohorts (which select for symptomatic families), providing a more conservative but more generalizable risk figure.

Practical Actions

For heterozygous carriers of Ser148Pro, the clinical priorities are: documentation and disclosure (this result must be in medical records before any surgery, hospitalization, pregnancy, or hormonal therapy); thrombophilia specialist evaluation; and avoidance of high-risk provoking exposures. Routine (unprovoked) anticoagulation is not indicated for asymptomatic carriers, but high-risk situational prophylaxis during surgery, immobility, and pregnancy is strongly supported. Women considering combined hormonal contraceptives face multiplicative risk and should choose non-estrogen methods. Hematology consultation should precede any high-stakes decisions. First-degree relatives carry a 50% chance of inheriting the variant and benefit from cascade genetic testing before their first thrombotic event.

Interactions

The most clinically significant interaction is with Factor V Leiden (rs6025, F5 R506Q)88 Factor V Leiden (rs6025, F5 R506Q)
The most common inherited thrombophilia, affecting ~5% of Europeans; compound heterozygosity with AT deficiency has been associated with much higher VTE risk than either alone. Double thrombophilia — inheriting both an antithrombin mutation and Factor V Leiden — produces additive or synergistic risk elevation. The prothrombin G20210A variant (rs1799963) represents a second compounding thrombophilic interaction. Any AT-deficient individual found to co-inherit one of these variants should have risk discussed by a hematologist as a combined clinical picture, not as two separate genetic findings.

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-carrier Normal

Normal antithrombin function — no Ser148Pro variant detected

You carry two copies of the common reference allele at rs121909569. The Ser148Pro pathogenic variant in SERPINC1 is not present in your genome at this position. Your antithrombin III gene at this locus is expected to produce structurally normal antithrombin protein with full heparin-binding and reactive site activity. This is the overwhelmingly common genotype — the G risk allele is absent in European and African population databases and appears at approximately 0.017% frequency in East Asian populations, making non-carrier status universal in most ancestry groups.

AG Carrier Carrier

Heterozygous carrier of likely pathogenic SERPINC1 Ser148Pro — elevated lifetime VTE risk

Type II pleiotropic effect antithrombin deficiency is the most severe of the three type II subtypes because it compromises antithrombin by two mechanisms simultaneously: reduced heparin-binding (which normally accelerates thrombin/Factor Xa inhibition 1,000-fold) and reduced reactive-site efficiency (the baseline serpin inhibitory mechanism).

Key provocation-specific risks for heterozygous carriers:

  • Surgery and hospitalization: Perioperative VTE is a critical risk period. Antithrombin levels may need to be assessed pre-operatively; thromboprophylaxis with LMWH should be documented and planned before elective procedures.
  • Pregnancy: Antepartum VTE risk estimated at 7.3% and postpartum risk at 11.1% (Croles et al., BMJ 2017). ACOG and ACCP guidelines classify AT deficiency as high-risk and recommend antepartum plus postpartum LMWH prophylaxis for carriers with a personal or family VTE history.
  • Estrogen-containing contraceptives and hormone therapy: Estrogen-based contraceptives (combined oral contraceptives, patch, ring) and menopausal hormone therapy increase VTE risk 3–5 fold in the general population; this risk is multiplied in AT-deficient carriers. Non-estrogen alternatives are strongly preferred.
  • Prolonged immobility: Long-haul flights and extended bed rest are documented VTE triggers; carriers should use compression socks and remain physically active during travel when possible.

Antithrombin concentrate (plasma-derived or recombinant) is available for perioperative or peripartum prophylaxis in AT-deficient individuals. This is typically coordinated through a hematologist or thrombosis specialist in anticipation of high-risk procedures or delivery.

GG Homozygous (Unconfirmed) Homozygous

Apparent homozygosity for the Ser148Pro SERPINC1 variant — requires urgent specialist verification

Antithrombin is essential to survival. Animal models of complete antithrombin deficiency are characterized by fulminant disseminated intravascular coagulation and early death. No confirmed biallelic SERPINC1 pathogenic variant carriers with Ser148Pro specifically have been reported in the published literature.

If this result is technically confirmed, it would likely require: - Immediate hematology evaluation with emergency antithrombin activity measurement (expected to be near zero) - Consideration of antithrombin concentrate therapy - Full thrombophilia workup and imaging to assess for thrombotic events

Given the extreme rarity, the first step must be confirming the variant call by Sanger sequencing or a second independent next-generation sequencing panel from an accredited clinical laboratory.