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49 p.-2 fig.-2 tab., Genetic variability in the complement system and its association with disease has been known for more than 50 years, but only during the last decade have we begun to understand how this complement genetic variability contributes to the development of diseases. A number of reports have described important genotype-phenotype correlations that associate particular diseases with genetic variants altering specific aspects of the activation and regulation of the complement system. The detailed functional characterization of some of these genetic variants provided key insights into the pathogenic mechanisms underlying these pathologies, which is facilitating the design of specific anti-complement therapies. Importantly, these analyses have sometimes revealed unknown features of the complement proteins. As a whole, these advances have delineated the functional implications of genetic variability in the complement system, which supports the implementation of a precision medicine approach based on the complement genetic makeup of the patients. Here we provide an overview of rare complement variants and common polymorphisms associated with disease and discuss what we have learned from them., SRdeC is supported by the Spanish “Ministerio de Economía y Competitividad/FEDER” [SAF2015-66287-R] and the Autonomous Region of Madrid [S2017/BMD-3673]. SRdeC is member of the "CIB Intramural Program “Molecular Machines for Better Life” (MACBET)". MLT is supported by the Spanish “Ministerio de Economía y Competitividad/FEDER” [PI15-00255]. EGdeJ is supported by the Spanish “Ministerio de Economía y Competitividad/FEDER” [SAF2014-52339-P]. SRdeC and EGdeJ are also supported by the “Fundación Inocente Inocente” (Madrid, Spain).