IDH2 encodes a mitochondrial NADP(+)-dependent isocitrate dehydrogenase that catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (alpha-ketoglutarate) in the tricarboxylic acid (TCA) cycle, where it supports cell metabolism and energy production. Cancer-associated alterations in its catalytic site confer a gain-of-function neomorphic activity that converts alpha-ketoglutarate into the oncometabolite D-2-hydroxyglutarate, which promotes tumor development by inhibiting enzymes involved in DNA and histone demethylation, adaptation to hypoxia, and collagen maturation. As an oncogene, IDH2 is associated with hematologic malignancies, particularly acute myeloid leukemia, as well as solid tumors such as gliomas and cholangiocarcinomas.

IDH2 drives cancer through gain-of-function mutations in its catalytic site, so this deep intronic variant—with no amino-acid change and no predicted splice impact (SpliceAI max delta 0.003)—does not fit the gene's established oncogenic mechanism. Its classification as a variant of uncertain significance reflects the lack of evidence for either a disease-causing or a benign effect.