Background: Genetic polymorphisms in the HEXA gene are associated with a neurodegenerative disorder called Tay-Sachs disease (TSD) (GM2 gangliosidosis type 1). This study aimed to predict the possible pathogenic SNPs of this gene and their impact on the protein using different bioinformatics tools. Methods: SNPs retrieved from the NCBI database were analyzed using several bioinformatics tools. The different algorithms collectively predicted the effect of single nucleotide substitution on both structure and function of the hexosaminidase A protein.Results: Fifty nine mutations were found to be highly damaging to the structure and function of the HEXA gene protein.Conclusion: According to this study, thirty two novel nsSNP in HEXA are predicted to have possible role in Tay-Saches Disease using different bioinformatics tools. Our findings could help in genetic study and diagnosis of Tay-Saches Disease.Keywords: Tay-Sachs disease (TSD), GM2 gangliosidosis, hexosaminidase A, HEXA, a neurodegenerative disorder, bioinformatics, single nucleotide polymorphisms (SNPs), computational, insilico. ganglioside which is caused by mutations in HEXA gene the highest concentration of GM2 ganglioside found in neuronal cells and they are the main glycolipids of neuronal cell's plasma membranes responsible of the normal cellular activities. Patients with HexA deficiency suffer from GM2 ganglioside accumulates inside neural's lysosomes. Therefore, HexA deficiency primarily affects the nervous system [1,2,4,[6][7][8][9][10][11][12][13][14].According to the disease onset age, TSD is differentiated into three types which are: acute infantile, juvenile, and late-onset. Acute infantile TSD is the most common type. It causes progressive weakness and motor skills lost in the infected infants. This progression occurs between the ages of six months to three years. In addition, the infected infant progressively suffers from diminished attentiveness and an exaggerated startle response. As TSD continues to destroy the brain infant suffers from seizures, blindness, and death which usually occurs before four years of age [8,9,11,[13][14][15].The human HEXA gene [OMIM *606869] encodes the alpha subunit of the lysosomal hexosaminidase A isozyme (HexA) which is located on chromosome 15 q23-q24 and contains 14 exons. More than two hundred mutations have been reported in the HEXA gene to cause TSD and its variants. These mutations include single base substitutions, small deletion, duplications, insertions splicing alterations, complex gene rearrangement, partial large duplications, partial deletion, splicing mutations, nonsense mutations and missense mutations that lead to the disruption of transcription, translation, folding, dimerization of monomers and catalytic dysfunction of HexA protein [4,8,11,15,16].