CytoSIP (SNPs, Interfaces, Phenotypes) comprehensively characterizes the most promising surface regions for targeted drug discovery on the structure of all cytokines and cytokine receptors (CK/CKR) in humans. The CR/CKR atlas developed herein also features a wealth of annotations, including CK/CKR genotype variants, protein structure complexes, and disease phenotypes, to increase its usability and range of applications. The database introduces a unique tri-level SIP data model (atom-molecule-organism) to link genotype variants that causes missense mutation (atomic level) to disease phenotypes (organism level) using protein structure (complexes) as an underlying framework (molecule level). Crafting a framework that can bridge genotype with phenotype not only provides a panoramic view towards the mechanism of action for cytokines and their receptors, but also accelerates the process of engineering therapeutic agents targeting cytokines or cytokine receptors.