rs9332736 — C2 28bp deletion (type I C2 deficiency)

C2 Type I Deficiency — The Null Allele at Europe's Most Common Complement Defect

Complement component C2¹¹ Complement component C2
C2 is a serine protease that forms the catalytic subunit of the classical C3 convertase, the enzymatic complex that amplifies complement activation sits at the intersection of innate immunity and autoimmune regulation. When an antibody-antigen complex or dying cell activates the classical complement pathway, C1q recruits C1r and C1s, which cleave C4 and then C2 into fragments that assemble the C4b2a complex — the classical C3 convertase — which drives opsonisation, immune complex clearance, B-cell activation, and the membrane attack complex. C2 is encoded in the HLA class III region on chromosome 6p21.3, a gene-dense immunological locus shared with complement factor B (CFB), C4A, C4B, and TNF.

The rs9332736 variant represents a 28-base-pair deletion in the sixth exon of C2 — specifically beginning 9 base pairs upstream of the exon 6 3'-splice site — that causes complete exon 6 skipping during pre-mRNA processing. The resulting frameshift introduces a premature stop codon, and no functional C2 protein is produced. People who inherit two copies of this deletion (homozygous) have complete C2 deficiency — undetectable serum C2 and a dramatically impaired classical complement pathway. This is type I C2 deficiency²² type I C2 deficiency
type I = no detectable protein; type II = protein made but secretion blocked, the most common form, accounting for the vast majority of all C2-deficient individuals. With a homozygous frequency of approximately 1 in 20,000 in Western Europe³³ 1 in 20,000 in Western Europe, it is the most common inherited complement deficiency in people of European descent.

The Mechanism

The deletion spans 28 base pairs beginning near the 3'-end of exon 6. This position disrupts the intron-exon boundary recognition sequence, causing the spliceosome to skip exon 6 entirely during pre-mRNA processing. The resulting transcript lacks 134 base pairs (all of exon 6), shifting the reading frame and generating a premature stop codon shortly downstream. No stable C2 protein is made — not a truncated form, not a misfolded protein, simply nothing. This is why the variant is classified as type I (null) rather than type II (secretion-blocked) deficiency.

The deletion allele travels almost exclusively on a specific extended HLA haplotype: HLA-A25, B18, BfS, C4A4, C4B2, DRw2⁴⁴ extended HLA haplotype: HLA-A25, B18, BfS, C4A4, C4B2, DRw2
also written as HLA-A*2501, B*1801, DRB1*1501 in modern nomenclature; the DRw2/DR2 designation is now DR15. More than 90% of C2-deficient individuals worldwide carry this ancient haplotype, indicating a single founding event — the deletion arose once in European prehistory and has been propagating on the same chromosomal block ever since. The HLA-B18 association provides a useful clinical screen when molecular typing is unavailable: HLA-B18 positivity raises the pre-test probability of C2 deficiency substantially.

Heterozygous carriers (one deletion allele) produce roughly 50% of the normal serum C2 level. This partial deficiency is sufficient for normal complement function in most circumstances — the pathway has redundant amplification capacity — but becomes clinically relevant when combined with other complement gene deficiencies, particularly low C4A gene copy number.

The Evidence

The Swedish C2 deficiency cohort⁵⁵ Swedish C2 deficiency cohort
40 homozygous-deficient patients from 33 families, followed over 25 years with 96% follow-up completeness provides the clearest picture of the homozygous phenotype. Of 40 patients: 57% experienced at least one episode of invasive bacterial infection, predominantly Streptococcus pneumoniae⁶⁶ Streptococcus pneumoniae
pneumococcus, the primary encapsulated pathogen whose polysaccharide capsule requires complement-mediated opsonisation for efficient clearance septicemia or meningitis. 25% developed SLE, and a further 17.5% developed undifferentiated connective tissue disease or vasculitis — a combined autoimmune burden of over 40%. Ten acute myocardial infarctions occurred across six patients, and the study found a significant association between C2 deficiency and atherosclerosis, a connection attributed to impaired immune complex clearance and chronic low-grade inflammation.

Notably, severe infections clustered in infancy and childhood before protective immunity was established, while autoimmune disease emerged in adulthood. This temporal pattern underscores the complementary roles of C2: early in life, complement opsonisation is the primary defence against encapsulated bacteria; in adulthood, complement-mediated clearance of apoptotic debris and immune complexes becomes critical for preventing autoimmunity.

The European allele frequency⁷⁷ European allele frequency
28bp deletion allele at ~0.7% in Caucasians is substantially enriched among SLE patients: a 1994 case-control study found an allele frequency of 0.0246 in Caucasoid SLE patients versus 0.0070 in controls (p < 0.05), a 3.5-fold enrichment. The deletion was entirely absent in both African-American SLE patients and African-American controls, confirming the European specificity of this variant⁸⁸ European specificity of this variant.

For heterozygous carriers, risk is modest at the single-locus level but interacts strongly with C4A copy number. A Scandinavian cohort of 958 SLE patients, 911 primary Sjögren's syndrome patients, and 2,262 healthy controls⁹⁹ Scandinavian cohort of 958 SLE patients, 911 primary Sjögren's syndrome patients, and 2,262 healthy controls found that heterozygous C2 deficiency combined with low C4A copies conferred an OR of 10.2 (95% CI 3.5–37.0) for SLE and OR 13.0 (95% CI 4.5–48.4) for primary Sjögren's syndrome. Disease onset was 7 years earlier in SLE and 12 years earlier in Sjögren's syndrome among carriers. Plasma C2 levels were measurably reduced (p = 2 × 10⁻⁹) and classical pathway function was impaired (p = 0.03).

Practical Implications

For homozygous DD individuals, the clinical management is clear: immunisation against the three major encapsulated pathogens (pneumococcus, meningococcus, Haemophilus influenzae type b) substantially reduces infection risk. Pneumococcal vaccination should use both conjugate (PCV20 or PCV15+PPSV23) and polysaccharide formulations to maximise coverage; meningococcal vaccination should cover serogroups A, C, W, Y and B. Booster schedules should be maintained. Prompt antibiotic treatment for fever or suspected invasive infection is critical. Immunologists and haematologists familiar with complement deficiency should be involved in care, particularly during childhood.

For heterozygous DI carriers in the general population, single-locus risk is low and no specific action is required beyond awareness. The interaction with C4A copy number (see Interactions section) becomes relevant when autoimmune symptoms develop or when family history suggests complement deficiency.

Interactions

The key interaction is between the C2 deletion and C4A copy number. C4A and C4B are also encoded in the HLA class III region, and low C4A copy number is common in Europeans. When heterozygous C2 deficiency (DI genotype) combines with low C4A dosage, the combined classical complement pathway deficiency is severe enough to substantially impair immune complex clearance, driving the OR 10-13 autoimmune risk described above. This interaction is clinically actionable: patients with early-onset lupus or Sjögren's syndrome who carry the DI genotype should be tested for C4A copy number to assess combined complement pathway function.

The C2 28bp deletion haplotype (A25-B18-DR15) is distinct from the H10 protective haplotype tagged by C2 E318D (rs9332739) and CFB L9H (rs1270942). These are different haplotypes in the same genomic region: the 28bp deletion allele is null (no C2 protein), while E318D is a benign missense change that tags a complement-protective signal for AMD. An individual can carry the E318D protective C allele on one chromosome and the 28bp deletion on the other — they are independent.