During the 2024-2025 influenza season in Auvergne-Rh?ne-Alpes, France, a genetically distinct cluster of A(H3N2) viruses within subclade J.2.2 was found to be significantly overrepresented in hospitalized patients compared with community patients. Circulating mainly in November and December 2024, this genetically distinct cluster harboured HA1:G62R and S145N mutations, both linked to immune escape, as well as P239Q, located near key antigenic sites and warranting further investigation. The findings highlight the importance of monitoring influenza genome diversity in both hospital and community settings to identify emerging genetically distinct clusters with potential for increased severity.