rs28362944 — SERPING1

5' UTR variant in C1-inhibitor gene that promotes partial exon 2 skipping, reducing C1-INH expression and acting as a severity modifier for complement-mediated inflammatory conditions

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SERPING1 c.-21T>C — The Quiet Splice That Amplifies Inflammation

Twenty-one nucleotides upstream of the start codon in exon 2 of SERPING1, a single T-to-C change alters how the cell reads the message for C1-inhibitor11 C1-inhibitor
A serine protease inhibitor (serpin) encoded by SERPING1 on chromosome 11; the primary brake on the complement classical/lectin pathways and the kallikrein-kinin system, controlling bradykinin production. This variant, rs28362944 (c.-21T>C), sits in the 5' untranslated region of the gene — a region that does not change the protein sequence but powerfully governs how efficiently the gene is spliced and translated. Unlike the nearby coding variant rs4926 (Val480Met), this SNP acts at the RNA level: when the C allele is present, a fraction of SERPING1 transcripts skip exon 2 entirely.

The Mechanism

The 5' UTR of a gene is the stretch of mRNA between the transcription start site and the first codon. Its sequence influences mRNA splicing22 mRNA splicing
The process of removing introns and joining exons; exonic sequences near splice sites contain regulatory elements (exonic splicing enhancers and silencers) that guide the spliceosome, secondary structure, and translational efficiency. Position c.-21 sits just inside exon 2 of SERPING1.

Duponchel et al. 200633 Duponchel et al. 2006
Duponchel C et al. Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH. Human Mutation, 2006 used transfected HepG2 and Hep3B hepatoma cells — the liver cells that produce most circulating C1-INH — to demonstrate that the C allele at c.-21 causes low but significant levels of exon 2 skipping. Skipping exon 2 disrupts the open reading frame downstream, leading to a truncated or degraded transcript.

C1-INH is the only known inhibitor of the classical and lectin complement pathways and the contact activation (kallikrein-kinin) system. When its output falls, the kallikrein-kinin cascade runs unchecked: plasma kallikrein cleaves high-molecular-weight kininogen to release bradykinin, a potent vasodilator and vascular permeability factor.

The Evidence

The foundational functional study is Duponchel et al. 2006 (PMID 16470590), which established that the c.-21C allele promotes exon 2 skipping in liver cells and proposed it as a severity modifier rather than a primary disease allele. The C allele is common in European populations (~4.7% allele frequency) and extremely rare in East Asian populations.

In the clinical genetics literature, rs28362944 appears consistently as one of five modifier variants in the SERPING1/complement pathway. Parsopoulou et al. 202244 Parsopoulou et al. 2022
Parsopoulou F et al. Searching for Genetic Biomarkers for Hereditary Angioedema Due to C1-Inhibitor Deficiency. Frontiers in Allergy, 2022 studied 233 HAE patients and found that TC or CC genotype carriers showed a 2.5-fold increased probability of requiring long-term prophylactic treatment (p = 0.012), rising to 4.2-fold among those whose primary SERPING1 variant was a missense mutation (p = 0.02). This modifier effect is independent of the primary disease allele.

Grombirikova et al. 202355 Grombirikova et al. 2023
Grombirikova H et al. Systematic Approach Revealed SERPING1 Splicing-Affecting Variants to be Highly Represented in the Czech National HAE Cohort. Journal of Clinical Immunology, 2023 confirmed in the Czech national HAE cohort that when the c.-21C allele sits in trans (on the opposite chromosome) with a causal SERPING1 variant, it is significantly associated with earlier age of onset (p = 0.024), higher annual attack frequency (p = 0.018), and higher clinical severity scores (p = 0.048). This demonstrates a gene-dosage amplification effect: the C allele does not cause disease alone but consistently worsens outcomes when C1-INH function is already compromised.

Genotype Interpretations

What each possible genotype means for this variant.

TT Standard C1-INH Splicing Normal

Reference genotype — full exon 2 retention and normal C1-inhibitor transcript output

The c.-21T allele maintains the local sequence context that the spliceosome reads as "include exon 2." Both copies of SERPING1 produce full-length mRNA under this genotype, including the exon 2 region that encodes part of the N-terminal signal peptide and early protein sequence. This genotype was the reference in the Parsopoulou 2022 HAE modifier study and in the Grombirikova 2023 Czech cohort analysis — meaning the severity effects reported for C allele carriers are expressed relative to TT individuals like you.

CT Reduced C1-INH Transcript Efficiency Intermediate

One copy of the exon-skipping allele — mildly reduced C1-inhibitor transcript yield

The Grombirikova 2023 Czech HAE cohort data showed that the c.-21C allele in trans with a causal SERPING1 variant was associated with earlier onset (p = 0.024) and higher attack frequency (p = 0.018).

CC Low C1-INH Transcript Output High Risk

Two copies of the exon-skipping allele — reduced C1-inhibitor transcript output from both alleles

In CC homozygotes, every SERPING1 transcript is produced from a gene copy carrying the exon 2 splicing-disrupting allele. The Duponchel 2006 functional study demonstrated that the C allele causes partial exon 2 skipping in hepatoma cells — cells that produce the majority of circulating C1-INH. With both alleles affected, the fraction of correctly spliced, translatable transcripts is lower than in either TT or TC genotypes.

Because CC homozygosity has a global frequency of ~0.002 (0.2%), published clinical data on this specific genotype are limited. However, the gene-dosage logic from heterozygote data — TC carriers showing 2.5-fold increased LTP probability in HAE contexts and significant associations with earlier onset and higher attack frequency — suggests CC homozygotes experience a compounded regulatory deficit.

In practice, CC carriers with no other SERPING1 pathogenic variant are unlikely to develop hereditary angioedema (which requires a primary loss- of-function mutation).