Identification and genomic characterization of BA.3.2: a highly divergent BA.3-related SARS-CoV-2 lineage from southern Africa

In November 2024, a highly divergent BA.3-related severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage, designated BA.3.2, was detected in South Africa, marking the first appearance of a BA.3-derived lineage in over 2 years. Phylogenetic reconstruction places BA.3.2 on an extended branch descending from ancestral BA.3, with no intermediate genomes detected, consistent with a prolonged period of unsampled or isolated evolution. Molecular clock analyses indicate accelerated divergence characteristic of a saltation event, whilst phylogeographic and demographic analyses point to a southern African origin followed by multiple independent exportations and evidence of ongoing global transmission. Relative to ancestral BA.3, BA.3.2 harbours 39 amino acid substitutions in the spike glycoprotein, two N-terminal domain deletions (Δ136-147 and Δ243-244), a four-residue insertion (ins214:ASDT), and a large deletion spanning ORF7a, ORF7b, and ORF8. The co-occurrence of D405N and R408S implies epistasis between these sites, whilst reversions R493Q and H505Y likely enhance ACE2 binding and antibody escape. Extensive remodelling across the spike, including loss of the C15-C136 disulphide bond and substitutions in the SD1 and SD2 domains, may influence spike stability, cleavage, and fusogenicity. The emergence and continued circulation of BA.3.2 underscores the ongoing potential for highly divergent SARS-CoV-2 variants to arise and spread globally. Despite its limited prevalence, the persistence of BA.3.2 alongside dominant lineages, together with evidence of more recent expansion, indicate that this lineage retains the potential to become of epidemiological concern under favourable conditions.