SAMD9L is an interferon-regulated antiviral protein that negatively regulates cell proliferation through suppression of growth factor signaling 1. It mediates growth inhibition by internalizing growth factor receptors and may facilitate endosome fusion, with localization to mitochondria and cytoplasm 2. Heterozygous germline gain-of-function (GoF) variants in SAMD9L cause multisystem syndromes characterized by pancytopenia, immunodeficiency, bone marrow failure, and progressive neurologic deficits including ataxia and cerebellar atrophy 13. Over 90% of patients carry missense GoF variants, though frameshift-truncating variants also exhibit GoF properties 1. SAMD9L variants account for approximately 8% of pediatric myelodysplastic syndrome (MDS) cases and are associated with increased interferonopathy signatures 45. A distinctive feature is somatic genetic rescue occurring in >60% of patients through monosomy 7 (which may be transient or progress to MDS/leukemia), compensatory somatic mutations, or uniparental disomy 7q—mechanisms that restore normal hematopoiesis but carry malignant progression risk 14. SAMD9L-associated autoinflammatory disease (SAAD) represents a specific phenotype with elevated interferon response gene signatures 2. Clinical management requires multidisciplinary care and genetic surveillance to distinguish disease remission from progression.