This study examines the association between SARS-CoV-2 genetic variants and hospitalization risk using data from 12,538 patients. The analysis uses XGBoost with SHAP and generalized linear mixed models to evaluate the impact of viral genomic variants, including B.1.1.7, AY.44, and AY.54, on hospitalization risk. Omicron is associated with lower hospitalization risk compared to prior variants. Variants at specific amino acid locations, including those in the Spike protein N-terminal domain and non-structural protein 14, are linked to hospitalization risk. The study also considers patient factors such as vaccination status, nMAb treatment, and comorbidities. Results indicate that genetic variants and patient characteristics collectively influence hospitalization risk. The study highlights the importance of considering both genetic and clinical factors in understanding SARS-CoV-2 outcomes. The findings suggest that certain amino acid changes, such as S_T95 and ORF1a_A2554, are associated with increased or decreased hospitalization risk. The study also identifies several lineages, including AY.44, as potentially associated with hospitalization. The results emphasize the need for further research to confirm these associations and understand the underlying mechanisms. The study underscores the importance of integrating clinical and genomic data to improve understanding of SARS-CoV-2 pathogenesis and inform public health strategies.This study examines the association between SARS-CoV-2 genetic variants and hospitalization risk using data from 12,538 patients. The analysis uses XGBoost with SHAP and generalized linear mixed models to evaluate the impact of viral genomic variants, including B.1.1.7, AY.44, and AY.54, on hospitalization risk. Omicron is associated with lower hospitalization risk compared to prior variants. Variants at specific amino acid locations, including those in the Spike protein N-terminal domain and non-structural protein 14, are linked to hospitalization risk. The study also considers patient factors such as vaccination status, nMAb treatment, and comorbidities. Results indicate that genetic variants and patient characteristics collectively influence hospitalization risk. The study highlights the importance of considering both genetic and clinical factors in understanding SARS-CoV-2 outcomes. The findings suggest that certain amino acid changes, such as S_T95 and ORF1a_A2554, are associated with increased or decreased hospitalization risk. The study also identifies several lineages, including AY.44, as potentially associated with hospitalization. The results emphasize the need for further research to confirm these associations and understand the underlying mechanisms. The study underscores the importance of integrating clinical and genomic data to improve understanding of SARS-CoV-2 pathogenesis and inform public health strategies.