Mixed Lineage Kinase Domain-like protein (MLKL) is the terminal effector protein in the inflammatory form of programmed cell death called ‘necroptosis’. The necroptotic pathway plays an important role in the progression of a variety of disease types; in various animal models, it was shown that inhibiting key necroptotic proteins (RIPK1/RIPK3) is efficacious in reducing severity of disease. Previous studies completed at WEHI uncovered constitutive activity was conferred to the mouse MLKL protein as a result of a single amino acid substitution, D139V, in the first brace helix of MLKL. Homozygous mice expressing this constitutively active MLKL protein exhibit lethality and present with a range of inflammatory phenotypes. In the human population 3 in 50 people are predicted to be heterozygous for two naturally occurring first brace helix missense polymorphisms MLKLS132P and MLKLR146Q. These high frequency polymorphisms fall in close proximity to the human equivalent of the lethal MlklD139Vmouse variant and map to an interface between the brace and pseudokinase domain of adjacent MLKL monomers. Preliminary analysis of Chronic Recurrent Multifocal Osteomyelitis (CRMO) cohorts indicates a 10-12-fold enrichment in the occurrence of brace helix variant compound heterozygotes relative to healthy controls. We examined a CRISPR-cas9 generated mouse model containing the mouse equivalent brace helix mutation MlklS131P, that when expressed in vitro exhibits a constitutively active phenotype. MlklS131P/S131P homozygotes presented with deficits in circulating blood cell numbers and serological features of inflammatory disease.