Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1. Display omitted •The effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1•BA.2 is resistant to BA.1-induced humoral immunity•The BA.2 spike is more fusogenic than BA.1 spike•BA.2 spike-bearing virus is more pathogenic than BA.1 spike-bearing virus Yamasoba and G2P-Japan Consortium et al. elucidate the characteristics of SARS-CoV-2 Omicron variant BA.2—transmissibility, immune resistance, virological property, and pathogenicity. The effective population number of BA.2 is higher than that of BA.1, and the antigenicity of BA.2 is different from that of BA.1. The BA.2 spike is more fusogenic than the BA.1 spike, and notably, the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. This multiscale investigation suggests the potential risk of BA.2 to global health.