rs201363394 — SERPING1 Arg400Cys

Pathogenic missense variant in SERPING1 encoding C1-inhibitor; the Arg400Cys substitution disrupts protein folding and causes hereditary angioedema type 1 through C1-INH deficiency — heterozygous carriers develop recurrent angioedema attacks, while the rare homozygous state produces severe HAE with additional complement depletion

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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.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

No Arg400Cys variant detected — normal C1-inhibitor function expected

You carry two copies of the common C allele at rs201363394 and do not carry the Arg400Cys pathogenic variant in SERPING1. Your C1-inhibitor gene at this position is intact and encodes normal Arg400, consistent with normal C1-INH production and function. This variant accounts for only a tiny fraction of HAE cases globally — the vast majority of people carry CC at this position and have no hereditary angioedema risk from this specific variant.

CT Carrier / HAE Type 1 Carrier

One copy of Arg400Cys — heterozygous SERPING1 pathogenic variant causing hereditary angioedema type 1

HAE attacks in heterozygous SERPING1 pathogenic variant carriers are bradykinin-mediated and do not respond to antihistamines, corticosteroids, or epinephrine — the standard treatments for allergic angioedema. This diagnostic distinction is critical: carriers presenting to emergency departments with acute laryngeal or severe abdominal attacks require specific HAE-targeted therapy (C1-INH concentrate, icatibant, or ecallantide) rather than conventional allergy management.

Attack triggers commonly include stress, trauma, infections, hormonal changes (especially estrogen-containing contraceptives or pregnancy), and dental/surgical procedures. Many carriers have first attacks in adolescence, though onset can occur at any age. Abdominal attacks are frequently misdiagnosed as acute abdomen or psychiatric illness before HAE is recognized.

Long-term prophylaxis with lanadelumab or berotralstat substantially reduces attack frequency and should be discussed with a HAE specialist based on attack burden and quality of life impact. All first-degree relatives (parents, siblings, children) have a 50% probability of carrying the same variant and should be offered targeted genetic testing and cascade screening with C1-INH and C4 measurement.

TT Homozygous Homozygous

Two copies of Arg400Cys — homozygous SERPING1 pathogenic variant producing severe HAE

The homozygous Arg400Cys state eliminates functional C1-inhibitor production from both alleles, resulting in uninhibited activity of C1r, C1s, plasma kallikrein, and factor XIIa. C4 and C1q are both depleted by continuous unregulated complement activation — distinguishing this from typical heterozygous HAE type 1 where C1q is usually preserved. The clinical consequence is more frequent, more severe attacks with potentially poorer response to replacement-based therapies.

Confirmed homozygous carriers require immediate referral to a specialist HAE center with experience managing complex presentations. Management may require more frequent C1-INH prophylaxis dosing, combination approaches, or access to clinical trials for refractory HAE. Genetic counseling is essential, as all children of a homozygous carrier will inherit at least one pathogenic allele (50% probability of being heterozygous, 50% homozygous if the partner is an obligate carrier; 100% heterozygous if the partner is CC at this position).