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Simple Summary We have analyzed a panel of 88 pediatric medulloblastoma tumors for exon 3 mutations from the CTNNB1 gene and identified eight missense point-mutations and one in-frame deletion. We describe and functionally characterize a novel CTNNB1 in-frame deletion (c.109-111del, pSer37del, ΔS37) found in a pediatric patient with a classic medulloblastoma, WNT-activated grade IV (WHO 2016). To the best of our knowledge, this mutation has not been previously reported in medulloblastoma, and it is uncertain its role in the disease development and progression. Our analysis discloses gain-of-function properties for the new ΔS37 β-catenin variant. Abstract Medulloblastoma is the primary malignant tumor of the Central Nervous System (CNS) most common in pediatrics. We present here, the histological, molecular, and functional analysis of a cohort of 88 pediatric medulloblastoma tumor samples. The WNT-activated subgroup comprised 10% of our cohort, and all WNT-activated patients had exon 3 CTNNB1 mutations and were immunostained for nuclear β-catenin. One novel heterozygous CTNNB1 mutation was found, which resulted in the deletion of β-catenin Ser37 residue (ΔS37). The ΔS37 β-catenin variant ectopically expressed in U2OS human osteosarcoma cells displayed higher protein expression levels than wild-type β-catenin, and functional analysis disclosed gain-of-function properties in terms of elevated TCF/LEF transcriptional activity in cells. Our results suggest that the stabilization and nuclear accumulation of ΔS37 β-catenin contributed to early medulloblastoma tumorigenesis.