The spike (S) glycoprotein of coronaviruses is essential for binding of the virus to the host cell at the beginning of the infection process. The target protein is also a major immunogen and a possible target for entry inhibitors. The SARS-CoV-2 spike (S) protein is a large type I transmembrane protein composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain (RBD) responsible for binding to the host cell receptor angiotensin-converting enzyme 2 (ACE2). Several mutants of the spike protein are known. A mutation first discovered in Denmark, called “Cluster 5”, also known as the ΔFVI-spike, is related to four genetic changes. This mutation (Y453F) is located in a conservative region of the RBD directly involved in ACE2 binding and thereby could have implications for viral fitness, transmissibility, and antigenicity.