Advanced sequencing technologies enable rapid detection of sequence variants, aiming to uncover the molecular foundations of human genetic disorders. The challenge lies in interpreting the influence of new exome variants that lead to diverse phenotypes. Our study introduces a detailed, multi-tiered method for assessing the impact of novel variants, particularly focusing on the zinc finger protein 1 (ZPR1) gene. Herein, we employed a combination of variant effect predictors, protein stability analyses, and the American College of Medical Genetics and Association of Molecular Pathology (ACMG/AMP) guidelines. Our structural analysis pinpoints specific amino acid residues in the ZPR1 zinc finger domains that are sensitive to changes, distinguishing between benign and disease-causing coding variants using rigorous in silico tools. We examined 223 germline ZPR1 exome variants, uncovering significant ethnic disparities in the frequency of heterozygous harmful ZPR1 variants, ranging from 0.04% in the Ashkenazi Jewish population to 0.34% in African/African Americans. Additionally, the discovery of three homozygous carriers in European and South Asian groups suggests a higher occurrence of ZPR1 variants in these demographics, meriting further exploration. This research provides insights into the prevalence and implications of amino acid substitutions in the ZPR1 protein.