Gastrointestinal schwannomas are molecularly and histologically distinct from their non-gastrointestinal counterparts, lacking NF2 alterations, although the primary drivers of these tumors are barely understood. A recent study has identified SOX10 in-frame insertions in schwannomas, particularly in intracranial non-vestibular lesions, whereas their role in gastrointestinal schwannomas remains unexplored. Whole exome sequencing of 15 gastrointestinal and two non-gastrointestinal schwannomas revealed recurrent SOX10 in-frame insertions in 14 gastrointestinal cases (93%) without other nerve sheath tumor-related alterations, such as NF2 mutations or SH3PXD2A::HTRA1 fusions (~14% in non-gastrointestinal cases). The prevalence, mutation spectrum, and specificity of SOX10 insertions were validated using Sanger sequencing in a large cohort comprising 61 gastrointestinal and 98 non-gastrointestinal schwannomas, as well as 110 non-schwannomatous mesenchymal and melanocytic neoplasms. SOX10 insertions, occurring within or near the high mobility group box domain, were significantly enriched in gastrointestinal schwannomas (91.8%) compared with non-gastrointestinal cases (5.1%). The most common insertion, p.Y173_Q174insKY, was present in 86.9% of gastrointestinal schwannomas but absent in non-gastrointestinal cases. Another recurrent insertion, p.P175_R176insKYQP, was rare and exclusively found in non-gastrointestinal schwannomas (3/98), while all non-schwannomatous controls were SOX10-normal. SOX10-inserted schwannomas exhibited histologic features characteristic of gastrointestinal schwannomas, including a microtrabecular arrangement of Schwann cells, peripheral lymphoid cuffs, and a lack of encapsulation. Both SOX10-inserted and SOX10-normal schwannomas demonstrated diffuse SOX10 immunoreactivity. The SOX10-inserted group was significantly associated with gastrointestinal locations (p