rs28362944 — SERPING1

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

See your personal result for SERPING1

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

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, producing a shorter, non-functional mRNA that is degraded rather than translated into protein.

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 — close enough to the exon 2 boundary that changing T to C disrupts an exonic splicing enhancer element.

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. The result is a haploinsufficiency-like effect: under conditions of immune challenge, a measurable fraction of C1-INH transcripts from the C allele are lost, reducing total C1-INH output at precisely the moment more inhibitor is needed.

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. At the blood-brain barrier, bradykinin excess increases permeability, allowing plasma proteins and immune cells to enter the CNS — a process that activates microglia and drives the neuroinflammatory cytokine environment implicated in sleep architecture disruption.

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, suggesting population-specific selective pressure on this regulatory site.

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 — and additive to — the primary disease allele, indicating the c.-21 site controls a separable regulatory layer of C1-INH expression.

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.

The sleep connection runs through the same neuroinflammatory pathway implicated by the companion variant rs4926. Farfara et al. 201966 Farfara et al. 2019
Farfara D et al. Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits. Glia, 2019 showed in mice that depleting C1-INH by ~83% was sufficient to cause measurable BBB permeability, microglial activation, elevated brain IL-1β and TNF-α, and depressive-like behavior. The SERPING1 locus was also identified by Jansen et al. 201977 Jansen et al. 2019
Jansen PR et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nature Genetics, 2019 as a genome-wide significant insomnia risk locus in 1.33 million individuals. While the Jansen GWAS tags both SERPING1 variants collectively at the locus level, the c.-21T>C RNA-level effect provides a mechanistically distinct route to reduced C1-INH availability during immune activation.

Practical Actions

Because this variant reduces C1-INH output at the RNA level during immune stress rather than continuously, the clinical relevance is highest during periods of acute infection, inflammation, or metabolic challenge — which are precisely the conditions that also disrupt sleep. Strategies that reduce the basal inflammatory load (particularly the complement and kallikrein-kinin pathways) give the reduced C1-INH reserve more headroom. Long-chain omega-3 fatty acids (EPA/DHA) inhibit pro-inflammatory eicosanoid production downstream of complement activation. For TC heterozygotes, the effect is modest and manageable. For CC homozygotes (rare, ~0.2% of the population), the combined exon-skipping burden from both alleles is more significant, though this genotype is so uncommon that published clinical data are limited.

Interactions

This variant acts at the RNA-expression level in the same gene as rs4926 (Val480Met), which acts at the protein-function level. Together, they represent two independent regulatory axes of C1-INH output from SERPING1: one affecting transcript integrity, one affecting protein stability under inflammatory stress. The combination of C allele at rs28362944 with A allele at rs4926 may produce compounded reduction in effective C1-INH availability, though direct compound-genotype data are limited in the published literature. Upstream in the same pathway, rs1801020 (F12 A46T) increases the rate of contact activation that C1-INH must suppress, and rs3733402 (KLKB1) modulates plasma kallikrein activity. Carrying modifier alleles at multiple nodes of this cascade compounds the neuroinflammatory risk.

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 under immune stress

In TC heterozygotes, one copy of SERPING1 contains the c.-21C allele that disrupts an exonic splicing enhancer near exon 2. Under basal (unstressed) conditions, this produces a low level of exon 2-skipped transcripts that are degraded. During acute immune activation — when the liver upregulates C1-INH production — the splicing machinery is more heavily engaged, and the proportion of aberrant transcripts from the C allele increases, reducing total C1-INH output at the time when it is most needed.

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). While TC carriers in the general population do not have the primary pathogenic variant, they carry a regulatory burden that can compound other sources of C1-INH pathway stress — including the companion coding variant rs4926 (A allele) and upstream pathway variants in F12 and KLKB1. The net effect is a modestly elevated neuroinflammatory baseline during illness.

CC Low C1-INH Transcript Output High Risk

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

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 under inflammatory stress 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. The complement and kallikrein-kinin pathways regulated by C1-INH include the primary upstream generator of bradykinin, which affects vascular permeability at the blood-brain barrier and the somnogenic cytokine environment.

In practice, CC carriers with no other SERPING1 pathogenic variant are unlikely to develop hereditary angioedema (which requires a primary loss- of-function mutation), but may experience a heightened neuroinflammatory baseline during illness and greater susceptibility to sleep disruption during and after immune activation events.