Rare molecular variants constitute an important but often under-recognized subgroup of gastrointestinal stromal tumors, with distinct biological and clinical characteristics that influence treatment sensitivity, resistance mechanisms, and clinical outcomes while underscoring the growing importance of comprehensive molecular diagnostics in routine clinical practice.

Comprehensive molecular diagnostics, including next-generation sequencing, enables accurate classification of rare gastrointestinal stromal tumor subtypes, improves risk stratification, and supports selection of the most appropriate targeted therapy, particularly in tumors lacking canonical KIT or platelet-derived growth factor receptor alpha mutations.

This review summarizes current evidence on rare molecular variants of gastrointestinal stromal tumors, highlights their biological and clinical significance, and provides a practical overview of contemporary molecular diagnostic strategies for identifying clinically actionable alterations.