To further understand the potential impact of HNSCC-associated MAPK1 hotspot mutations (p.E322K, p.D321N, and p.R135K) in relation to the ERK2 protein structure, we mapped the 3D locations of residues E322, D321, and R135 on the resolved X-ray crystallography structure of the human MAPK1 (ERK2) (the structure was resolved with an ATP competitive inhibitor 5-Iodotubercidin and the allosteric inhibitor peptide-type ERK2 inhibitor; PDB ID: 5AX3 (ref. 13); MMDB ID: 136379 (ref. 14)). Here, MAPK1 is linked to head and neck squamous cell carcinoma.