Central giant cell granuloma (CGCG) is a benign, localised osteolytic lesion of the jaw that is categorised into non-aggressive and aggressive subtypes. In contrast to non-aggressive CGCG, aggressive CGCG is characterised by pain, paraesthesia, root resorption, rapid growth, a size of >
5 cm, cortical perforation, or recurrence after surgical treatment. However, the nature of CGCG, especially aggressive CGCG, remains unclear. This study was performed to analyse the systematic and comprehensive characteristics of CGCG of the jaw, especially the aggressive subtype, and first explored the genetic variation of aggressive CGCG by whole-exome sequencing. In total, 42 CGCGs were analysed (including 25 non-aggressive and 17 aggressive subtypes). H3F3A mutations were not detected in these CGCGs through immunohistochemistry and Sanger sequencing. The inability to detect H3F3A mutations could help differentiate CGCG from giant cell tumour of bone, indicating the two diseases are not different stages of the same pathological entity. Additionally, fluorescence in situ hybridisation did not reveal USP6 gene rearrangement in CGCG, which could distinguish it from aneurysmal bone cysts, especially the solid type. Therefore, H3F3A mutation and USP6 gene rearrangement detection have great significance in the clinicopathological diagnosis of CGCG of the jaw in terms of their ability to exclude giant cell tumour of bone and aneurysmal bone cyst. Moreover, the whole-exome sequencing data indicated that LRP1B gene abnormalities might be related to the aggressive biological behaviour of CGCG, and that NOTCH4 mutation could be a novel therapeutic target for aggressive CGCG.