C1R encodes complement C1r, a serine protease that initiates the classical complement pathway by catalyzing the first enzymatic step of this immune cascade 123. C1R functions as part of the C1 complex, a multiprotein assembly that recognizes antigen-antibody complexes on pathogen surfaces 34. When C1q, the recognition subunit of C1, binds to IgG or IgM complexed with antigens, this interaction promotes C1R's autocatalytic activation through self-cleavage at a single Arg-Ile bond 561. Activated C1R then cleaves and activates C1S, the second protease in the classical pathway 57. The mechanism involves formation of a flexible Ca²⁺-dependent C1 complex where catalytic domains are strategically positioned within the C1q scaffold, though whether C1R activates C1S within single complexes or between neighboring complexes remains unclear 83. Beyond its canonical complement role, C1R has emerged as a plasma biomarker in sarcopenia, with elevated extracellular vesicle-associated C1R showing diagnostic potential 9. C1R deficiency is associated with periodontal Ehlers-Danlos syndrome type 1, highlighting its physiological importance 10.