Nearly 80% of ERK pathway activation can be attributed to B-Raf proto-oncogene, serine/threonine kinase (<i>BRAF</i> V600E), and mitogen-activated protein kinase kinase 1 (<i>MAP2K1</i>) variants, with <i>BRAF</i> V600E specifically detected in approximately 50% of pediatric LCH cases and associated with a higher risk of severe disease and treatment failure. Here, MAP2K1 is linked to Langerhans cell histiocytosis.