This study redefines the oncogenic paradigm of <i>SF3B1</i> mutations by demonstrating that distinct hotspot mutations exploit lineage-specific splicing vulnerabilities to drive tumorigenesis and establishes RAS activation as key mechanism underlying <i>SF3B1</i><sup>R625H</sup>-driven melanoma, positioning RAS pathway as tractable therapeutic target in <i>SF3B1</i>-mutant melanoma. This evidence concerns the gene SF3B1 and melanoma.