H3F3A K28M mutation (more commonly referred to as K27M) is a diagnostic parameter for the 2016 WHO-recognized entity, "Diffuse Midline Glioma H3 K27M-mutant", an astrocytic diffusely infiltrating tumor arising in the midline, typically within the brainstem, but also sometimes arising in the diencephalon or spinal cord. These tumors have a poor prognosis. The H3K27M alteration, which is characteristically heterozygous, leads to a decrease in overall H3K27me3 levels through dysregulation of the polycomb repressive complex 2 (PRC2), and a concurrent increase in H3K27 acetylation levels. Research is ongoing in an effort to develop ways to exploit this characteristic molecular alteration through targeted strategies.