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Highlights • First observation on the extensive deletion of amino acid residues in the C-terminal region of the E protein in some of the SARS-CoV-2 sequenced from the India. . • The deletion is outside the primer binding region of RTqPCR targeting E gene used in India in isolates from various states except Odisha, which had deletion in primer binding region. • Characteristic in-frame deletion in the E protein map to the homopentameric interface and PDZ binding motif (PBM) present in the C-terminal region of E protein. • The isolates with deletions belonged to different clades., The envelope glycoprotein (E) is the smallest structural component of SARS-CoVs; plays an essential role in the viral replication starting from envelope formation to assembly. The in silico analysis of 2086 whole genome sequences from India performed in this study provides the first observation on the extensive deletion of amino acid residues in the C-terminal region of the envelope glycoprotein in 34 Indian SARS-CoV-2 genomes. These amino acid deletions map to the homopentameric interface and PDZ binding motif (PBM) present in the C-terminal region of E protein as well as immediately after the reverse primer binding region as per Charité protocol in 26 of these genomes, hence, their detection through RT-qPCR may not be hampered and therefore E gene-based RT-qPCR would still detect these isolates. Eight genomes from the State of Odisha had deletion even in the primer binding site. It is possible that the deletions in the C-terminal region of E protein of these genomes are a result of adapting to a newer geographical area and host. The information on the clinical status was available only for 9 out of 34 cases and these were asymptomatic. However, further studies are indispensable to understand the functional consequences of amino acid deletion in the C terminal region of SARS-CoV-2 envelope protein in the viral pathogenesis and host adaptation.