Changes in hydrophobicity mainly promotes the aggregation tendency of ALS associated SOD1 mutants.

•Over 50% of SOD1 mutations are aggregation prone and the majority of them located in the buried region.•Aggregation of SOD1 mutants is primarily increased due to native hydrophobicity changes.•The loss of hydrogen bond between buried and exposed regions due to mutation destabilizes SOD1 structure and triggers aggregation.•The native sequence is essential to form the stable tertiary structure of SOD1 protein.