rs1064793917 — SERPING1

SERPING1 c.1169_1175del — A Seven-Base Deletion That Silences C1-Inhibitor

The SERPING1 gene encodes C1-inhibitor (C1-INH)¹¹ C1-inhibitor (C1-INH)
Serpin family G member 1 — a serine protease inhibitor that regulates the complement, contact activation, fibrinolytic, and coagulation pathways, keeping the body's inflammatory cascade under strict control. When C1-INH is absent or non-functional, the contact activation pathway generates bradykinin — a potent peptide that opens vascular endothelial junctions and forces fluid into surrounding tissues. The result is hereditary angioedema (HAE): unpredictable, recurrent episodes of severe swelling affecting the skin, gut, and airway, with laryngeal attacks carrying real mortality risk if untreated.

The c.1169_1175del variant removes seven nucleotides (AGTTCCA) from exon 8 of the SERPING1 coding sequence. This shifts the reading frame starting at codon 390 (lysine, p.Lys390fs) and creates a premature stop codon shortly downstream. The truncated transcript is almost certainly eliminated by nonsense-mediated mRNA decay, producing no functional C1-INH protein from that allele — the molecular hallmark of HAE Type I. HAE affects approximately 1 in 50,000–77,000 people globally²² 1 in 50,000–77,000 people globally
Guan et al. 2024 systematic review, 65 studies, 10,310 patients; prevalence range 0.13–1.6 per 100,000 across regions, with no significant ancestry differences.

The Mechanism

C1-INH is the dominant inhibitor of factor XIIa and plasma kallikrein³³ factor XIIa and plasma kallikrein
the two key enzymes of the contact activation pathway that ultimately produce bradykinin from high-molecular-weight kininogen, as well as complement proteases C1r and C1s. When one SERPING1 allele carries a frameshift, circulating C1-INH levels fall to roughly 30–50% of normal — insufficient to fully suppress kallikrein activity. Bradykinin surges drive episodes of submucosal and subcutaneous edema⁴⁴ submucosal and subcutaneous edema
Non-pitting swelling in the deep dermis and submucosa, not at the skin surface — which is why antihistamines and corticosteroids, which target mast-cell-driven allergic edema, are completely ineffective in HAE. Attacks commonly affect the face, hands, genitalia, and gastrointestinal tract (producing abdominal pain that mimics a surgical emergency), and the larynx — where swelling can obstruct the airway within hours.

HAE follows autosomal dominant inheritance⁵⁵ autosomal dominant inheritance
One mutant allele is sufficient to cause disease — the remaining functional allele cannot compensate for the 50% reduction in C1-INH. Each child of an affected parent has a 50% chance of inheriting the mutation. De novo mutations account for approximately 20–25% of cases, so a negative family history does not exclude the diagnosis.

The Evidence

The mortality data from HAE are stark. A landmark study by Bork et al.⁶⁶ Bork et al.
Journal of Allergy and Clinical Immunology, 2012 — 728 patients across 182 families found that 70 of 214 deceased patients died from laryngeal asphyxiation. Among those who died of asphyxiation, 63 had never received a HAE diagnosis — they lived on average 31 years shorter than diagnosed HAE patients who died from other causes. The systematic review by Guan et al.⁷⁷ Guan et al.
Orphanet Journal of Rare Diseases, 2024 — 65 studies, 10,310 patients quantified the overall asphyxiation mortality risk at 8.6%, with a mean diagnostic delay of 3.9 to 26 years. This diagnostic gap is where most preventable deaths occur.

The mutation spectrum of SERPING1 is broad. A Spanish cohort study by López-Lera et al.⁸⁸ López-Lera et al.
Molecular Immunology, 2011 — 59 families identified 52 distinct mutations, of which 15 (29%) were frameshifts. Frameshift mutations virtually always abolish protein production entirely (Type I HAE) rather than producing a dysfunctional protein (Type II). A Chinese cohort study of 97 HAE patients (Wang et al.⁹⁹ (Wang et al.
Hereditas, 2022) similarly found frameshifts accounting for 28.9% of SERPING1 mutations, confirming that frameshift variants represent the largest class after missense mutations.

Modern therapies have transformed HAE management. The HELP trial¹⁰¹⁰ HELP trial
Riedl et al., Allergy, 2020 — lanadelumab subcutaneously every 2–4 weeks showed 85.7–100% of patients achieved ≥50% attack reduction versus 26.8% on placebo, with 37.9–48.1% becoming completely attack-free. The APeX-2 trial¹¹¹¹ APeX-2 trial
Zuraw et al., JACI, 2021 — berotralstat 150 mg daily showed an oral kallikrein inhibitor reduced attacks from 2.35 to 1.31 per month (P<0.001). For acute attacks, icatibant¹²¹² icatibant
Cicardi et al., NEJM, 2010 — FAST-1/2 trials (a bradykinin B2 receptor antagonist) reduced time to symptom relief to 2.0–2.5 hours compared to 4.6–12.0 hours for control.

Practical Actions

The primary priorities for carriers are accurate diagnosis, access to on-demand acute treatment carried at all times, and an individualized prophylaxis plan developed with an HAE specialist. Laryngeal attacks follow a predictable progression: a predyspnea phase averaging 3.7 hours, then a dyspnea phase averaging 41 minutes, then rapid deterioration. Treatment must begin in the predyspnea phase — waiting for dyspnea is dangerous.

Estrogen-containing medications (oral contraceptives, hormone replacement therapy) precipitate and worsen HAE attacks by reducing C1-INH levels and increasing bradykinin production. ACE inhibitors block the enzyme that normally degrades bradykinin, dramatically increasing attack frequency, and are specifically contraindicated. All prescribing clinicians must be informed of the HAE diagnosis before initiating new medications.

Interactions

rs1064793917 is one of three SERPING1 pathogenic frameshift or missense variants in the GeneOps platform (see also rs1064793792 and rs201363394). Each independently causes HAE Type I through C1-INH deficiency. Compound heterozygosity — carrying two different SERPING1 pathogenic variants on opposite chromosomes — produces a phenotype equivalent to homozygosity (essentially complete C1-INH loss), documented in the literature for multiple SERPING1 variant pairs. Family members found to carry pathogenic variants at two independent SERPING1 loci require urgent HAE specialist management equivalent to the homozygous protocols.