The H7N9 influenza virus poses a significant threat to human health, and the mechanism by which it infects humans remains incompletely understood. Our investigation has unveiled significant insights into the role of glucosidase alpha, neutral C (GANC) gene in human H7N9 infections. Through whole genome sequencing (WGS), we identified five low-frequency functional and heterozygous variants of GANC strongly associated with human H7N9 infections compared to healthy controls. Furthermore, we observed a reduction in mRNA and protein expression of GANC following H7N9 virus infection in vitro and in vivo. Subsequent experiments involving GANC demonstrated the promotion of H7N9 virus replication in a stable strain with GANC overexpression. Conversely, GANC knockdown exhibited the ability to restrict influenza A virus (IAV) replication, including H7N9, H9N2, and H1N1, both in vitro and in vivo. This inhibition was mediated by GANC´s ability to promote the degradation of H7N9 hemagglutinin (HA). Moreover, we discovered that GANC knockdown facilitated the degradation of HA in a proteasome-dependent manner. The inhibition caused by GANC knockdown was mediated by promoting direct binding of HA with the proteasome 26S subunit, non-ATPase, 1 (PSMD1) and PSMD2. All five variants in the GANC gene reduced their ability to promote H7N9 virus replication, and also diminished the levels of GANC-induced HA protein expression. Our findings revealed a novel mechanism by which GANC inhibits the proteasome-dependent degradation of HA to promote H7N9 virus replication. These results suggest that GANC may play an important role in IAV replication.