rs201363394 — SERPING1 Arg400Cys

SERPING1 Arg400Cys — A Broken Brake on the Kinin System

C1-inhibitor is one of the body's most critical regulatory proteins — a molecular gatekeeper that prevents uncontrolled activation of the complement, contact, and fibrinolytic pathways. When C1-INH fails, the plasma kallikrein-kinin cascade runs unchecked, flooding tissues with bradykinin¹¹ bradykinin
A vasoactive peptide that binds bradykinin B2 receptors on endothelial cells, causing gaps between cells and the dramatic tissue swelling seen in HAE attacks. The rs201363394 T allele encodes Arg400Cys in the SERPING1 precursor (Arg378Cys in the mature protein), a substitution that disrupts C1-INH folding and function and causes hereditary angioedema type 1²² hereditary angioedema type 1
HAE type 1 is characterized by reduced C1-INH antigenic levels (<50% of normal); type 2 has normal or elevated antigen but dysfunctional protein; both types produce identical clinical attacks, a rare but life-threatening disease affecting approximately 1 in 50,000 people worldwide.

The Mechanism

SERPING1 encodes a serine protease inhibitor (serpin) whose reactive center loop presents a bait peptide to target proteases — C1r, C1s, plasma kallikrein, and factor XIIa. When these proteases take the bait, C1-INH forms a covalent inhibitory complex that permanently silences them. The Arg400 residue lies in a structurally critical position; the Arg400Cys substitution³³ Arg400Cys substitution
The arginine-to-cysteine change introduces a free thiol group that can form aberrant disulfide bonds, destabilizing the serpin fold and likely triggering premature polymerization or degradation rather than productive protease inhibition disrupts correct folding, reducing the pool of functional C1-INH available in plasma. The result is HAE type 1: circulating C1-INH antigen levels below 50% of normal, functional C1-INH activity correspondingly reduced, and constitutively low C4 complement (consumed by uninhibited C1r/C1s between attacks).

A homozygous case report⁴⁴ homozygous case report
The homozygous patient had completely absent functional C1-INH, absent C1q (consumed by unrestricted C1r/C1s), extremely severe HAE attacks, and poor response to standard therapy — establishing that two mutant copies compound the deficiency catastrophically demonstrated that homozygosity for Arg400Cys produces an extreme phenotype with depletion of C1q in addition to C4 — a finding that implicates the Arg378/400 position specifically in controlling the kinin pathway and highlights why even a single mutant copy is sufficient to cause clinical disease.

The Evidence

SERPING1 mutations cause HAE with autosomal dominant inheritance — a single mutant allele is sufficient to halve functional C1-INH output below the threshold required for normal pathway regulation. More than 700 SERPING1 variants⁵⁵ More than 700 SERPING1 variants
Ponard et al. 2020 catalogued 748 variants including 729 heterozygous and 10 homozygous probands, documenting missense changes at conserved reactive center loop residues as the mechanistically most impactful class have been documented in HAE patients, establishing C1-INH deficiency as the most common molecular basis for hereditary angioedema.

Cascade screening of first-degree relatives of HAE patients consistently identifies affected family members who are asymptomatic or mildly symptomatic — a 2025 cohort found 16 confirmed HAE cases among 89 first-degree relatives screened⁶⁶ found 16 confirmed HAE cases among 89 first-degree relatives screened
Hussain et al. identified cases using C1-INH and C4 measurements, confirming that biochemical screening can detect pathogenic variants before overt attacks develop, consistent with the expected 50% transmission probability per autosomal dominant inheritance. Three unscreened relatives died from laryngeal edema in that cohort — underscoring the mortality risk when diagnosis is delayed.

Practical Implications

For CT carriers (heterozygous), the clinical picture is classic HAE type 1: recurrent unprovoked swelling of the skin, gastrointestinal tract, or upper airway, typically beginning in adolescence and persisting lifelong. Attacks are bradykinin-mediated and do not respond to antihistamines, corticosteroids, or epinephrine⁷⁷ do not respond to antihistamines, corticosteroids, or epinephrine
This is the critical clinical distinction — HAE attacks superficially resemble allergic angioedema but fail to respond to standard allergic medications, leading to dangerous diagnostic delays. Laryngeal attacks carry significant mortality risk if untreated.

Three classes of on-demand therapy effectively abort acute attacks: C1-INH concentrates⁸⁸ C1-INH concentrates
Both plasma-derived and recombinant human C1-INH are approved and replace the deficient protein directly, icatibant (a subcutaneous bradykinin B2 receptor antagonist), and ecallantide (a plasma kallikrein inhibitor, US-only). Long-term prophylaxis with lanadelumab (a monoclonal antibody against plasma kallikrein) or berotralstat (an oral kallikrein inhibitor) dramatically reduces attack frequency. All HAE patients require access to on-demand medication and an emergency action plan for laryngeal attacks.

Interactions

rs201363394 is one of three SERPING1 missense variants in the GeneOps autoimmune batch. While each independently causes HAE type 1 through C1-INH deficiency, compound heterozygosity (carrying two different SERPING1 pathogenic variants on opposite chromosomes) produces a phenotype similar to homozygosity — essentially complete C1-INH functional loss. Family members who carry two independently segregating SERPING1 pathogenic alleles warrant urgent immunology referral and specialist HAE management from diagnosis.

The SERPING1 Arg400Cys variant does not interact with complement pathway genes (C2, C4, CFB) in any way that modifies management — the complement findings (low C4, occasionally low C1q in severe cases) are downstream consequences of C1-INH deficiency, not independent genetic risk factors requiring separate action at those loci.