<p>Hypophosphatasia (HPP) is a rare genetic disorder mainly affecting bone and tooth mineralization in patients due to <i>ALPL</i> gene mutations. Understanding genotype-phenotype correlations in HPP remains challenging due to different severities and the disease’s heterogeneity. To address this, we established a novel zebrafish animal model (<i>alpl</i>^wue7), which mimics severe HPP disease forms. To bypass limitations in human-based phenotypic classification of skeletal alterations in this transgenic line, we developed and trained an artificial intelligence (AI) model capable of image-based classification with 68% accuracy—an improvement of 79% over manual classification. Our AI model could successfully identify early developmental alterations independent of altered image magnification, coloration quality and executing scientists. Using attention rollout, we further visualized AI decision-making, revealing not only expected focus on early bone structures but also unexpected emphasis on the otoliths—parts of the zebrafish’s hearing and balancing organ. We see applications of our AI system in analyzing other skeletal disorder models as well as in providing an unbiased, high-throughput phenotypic rescue quantification assay for potential drug screening applications in zebrafish larvae. Overall, our findings establish an integrated platform for studying HPP and open new avenues for AI-assisted phenotyping and therapeutic discovery.</p>