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AP-4-HSP is characterized by features of both a neurodevelopmental and a degenerative neurological disease. To investigate the molecular mechanisms underlying AP-4-HSP and identify potential therapeutic targets, we conducted an arrayed CRISPR\/Cas9 loss-of-function screen of 8,478 genes, targeting the \u201cdruggable genome,\u201d in a human neuronal model of AP-4 deficiency. Through this phenotypic screen and subsequent experiments, key modulators of ATG9A trafficking were identified, and complementary pathway analyses provided insights into the regulatory landscape of ATG9A transport. Knockdown of\n                    <jats:italic>ANPEP<\/jats:italic>\n                    and\n                    <jats:italic>NPM1<\/jats:italic>\n                    enhanced ATG9A availability outside the\n                    <jats:italic>trans<\/jats:italic>\n                    -Golgi network, suggesting that they regulate ATG9A localization. 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