1Sepsis is a major contributor to mortality in paediatric patients. We investigated the human genetic underpinnings of sepsis by analysing a large paediatric cohort with blood-culture confirmed sepsis through multi-tiered genomic assessments: single-case, single-variant, single-gene, and protein pathway analyses. We designed and applied novel analytical methods to automate for unbiased interpretation. We identified two pathways involved in susceptibility to sepsis, which contained 50 genes (42 and 8, respectively) includingKIR2DL4,KIR3DL3,KLRD1,LILRA1,SIGLEC1, andSIRPG. These pathways are central to immune cell regulation, antigen processing, cellular signalling, and prevention of excessive inflammatory responses. A third enriched pathway of 22 genes was related to regulation of transcription. We additionally found 66 variants for inborn errors of immunity. Our findings highlight the influence of deleterious genomic variants on a shared immunological phenotype resulting in sepsis vulnerability in children. These insights lay a foundation for more personalised approaches to sepsis in children.