SPRED1 encodes a negative regulator of the RAS-MAPK signaling cascade, functioning as a tyrosine kinase substrate that inhibits growth-factor-mediated MAP kinase activation 1. The protein suppresses FGF-induced retinal lens fiber differentiation by inhibiting FGF-mediated ERK1/2 phosphorylation and attenuates actin stress fiber formation through inhibition of TESK1-mediated cofilin phosphorylation 2. SPRED1 also inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells. Functionally, SPRED1 acts as a tumor suppressor; its loss in mucosal melanomas (37% of cases) causes MAPK activation, increased cell proliferation, and resistance to KIT tyrosine kinase inhibitors 3. Clinically, SPRED1 loss-of-function mutations cause Legius syndrome, an autosomal dominant neurocutaneous disorder characterized by multiple café-au-lait macules, freckling, macrocephaly, and learning difficulties, but notably absent are neurofibromas and associated malignancies typical of NF1 1. SPRED1 mutations account for approximately 2.8-4% of patients presenting with pigmentary features suggestive of neurofibromatosis 45. Genetic heterogeneity in SPRED1 mutations, including missense, frameshift, nonsense, and copy number variants, shows no clear genotype-phenotype correlation 6.