One of the most important proteins for COVID-19 pathogenesis in SARS-CoV-2 is the ORF3a protein which is the largest accessory protein among other accessory proteins coded by the SARS-CoV-2 genome. The major roles of the protein include virulence, infectivity, ion channel activity, morphogenesis, and virus release. The coronavirus, SARS-CoV-2 is mutating rapidly, therefore, critical study of mutations in ORF3a is certainty important from the pathogenetic perspective. Here, a sum of 175 various non-synonymous mutations in the ORF3a protein of SARS-CoV-2 were identified in 7194 complete genomes of SARS-CoV-2 available in the NCBI database, and their corresponding effects in structural stability, and functions of ORF3a were studied. Broadly three different classes of mutations, such as neutral, disease, and mixed (neutral and disease) type mutations were observed. Consecutive mutations in ORF3a proteins are established based on the timeline of detection of mutations. Considering the amino acid compositions over the ORF3a primary protein sequences, twenty clusters were detected using the K-means clustering method. The present findings on 175 novel mutations of ORF3a proteins will extend our knowledge of ORF3a, a vital accessory protein in SARS-CoV-2, to enlighten on the pathogenicity of this life-threatening COVID-19.