HMG proteins are thought to play a significant role in various human disorders. Disruptions and rearrangements in the genes coding for some of the HMG proteins are associated with some common benign tumors. Antibodies to HMG proteins are found in patients with autoimmune diseases. The SRY gene on the Y Chromosome, responsible for male sexual differentiation, contains an HMG-Box domain.  A member of the HMG family of proteins, HMGB1, has also been shown to have an extracellular activity as a chemokine, attracting neutrophils and mononuclear inflammatory cells to the infected liver. The high-mobility group protein such as HMO1  alters DNA architecture by binding, bending and looping. Furthermore, these HMG-box DNA-binding proteins increase the flexibility of the DNA upon binding.
In mammalian cells, the HMG non-histone proteins can modulate the activity of major DNA repair pathways including base excision repair, mismatch repair, nucleotide excision repair and double-strand break repair.