Abstract Background C‐reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein‐altering (PA) and loss‐of‐function (LOF) variants in association with serum CRP, and to further explore the clinical relevance. Methods We included 161,430 unrelated participants of European ancestry from the UK Biobank. Of the rare (minor allele frequency