SETBP1 encodes a transcription factor with broad tissue expression involved in transcriptional regulation and DNA binding 1. The gene functions in both germline and somatic disease contexts through distinct molecular mechanisms. Germline loss-of-function variants cause haploinsufficiency-associated neurodevelopmental disorders, including SETBP1-haploinsufficiency disorder characterized by intellectual disability with loss of expressive language 2, and the severe pediatric condition Schinzel-Giedion syndrome 1. Somatic SETBP1 mutations drive myeloid malignancies, particularly enriched in atypical chr18 myeloid leukemia (aCML) and chr18 neutrophilic leukemia (CNL) 3. In aCML, SETBP1 mutations frequently co-occur with ASXL1 and other myeloid driver mutations, forming disease-specific mutational signatures 4. SETBP1 mutations also accumulate during disease progression from myelodysplastic syndrome to secondary CNL 5. Tissue-specific analysis reveals SETBP1 and its targets show coordinated expression patterns across 31 human tissues with distinct functional enrichment in transcriptional regulation and mitochondrial function 1. Germline variants additionally predispose to clonal hematopoiesis 6. SETBP1 mutations correlate with adverse prognosis in myeloid neoplasms, supporting its role as a clinically relevant molecular marker in diagnosis and risk stratification 3.