The structure of proteins impacts directly on the function they perform.Mutations in the primary sequence can provoke structural changes with consequent modification of functional properties. SARS-CoV-2 viral proteins have been extensively studied during the pandemic. Thus, a considerable body of data related to sequence and structure is available, enabling joint sequence-structure analysis. In this work, we focus on the SARS-CoV-2 S (Spike) protein and therelations between sequence mutations and structure variations, in order toshed light on the structural changes stemming from the position ofmutated amino acid residues in three different SARS-CoV-2 strains. We propose the use of Protein Contact Network (PCN) formalism able to: (i) get aglobal structural metric space and to compare various molecular entities and (ii) givea mechanistic explanation of the observed phenotype.PCNs have been used to compare sequence and structure of the α, δ and Omicron SARS-COV2 variants, and we found that omicron has a unique non random mutational Pattern that determines remarkable changes in structural properties.