FOXL2 encodes a forkhead-domain transcription factor essential for ovarian development and maintenance 1. It drives the differentiation of supporting gonadal cells during early ovarian development by downregulating coelomic epithelial markers and facilitating the transition toward gonadal-like cell identity 2. FOXL2 prevents testicular trans-differentiation by repressing SOX9 and maintains adult ovarian phenotype through a regulatory balance with DMRT1 3. The gene regulates diverse target genes involved in sex determination, steroidogenesis, cell-cycle progression, and apoptosis; FOXL2 also suppresses ESR1-mediated transcription and participates in SMAD3-dependent signaling. Germline FOXL2 mutations cause blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), an autosomal dominant condition characterized by premature ovarian insufficiency and eyelid defects, with over 100 variants identified 1. Reduced FOXL2 expression in ovarian tissue correlates with premature ovarian insufficiency in human subjects 4. A recurrent somatic C134W mutation, present in >90% of adult granulosa cell tumors, disrupts the balance between FOXL2-mediated apoptosis and GATA4/SMAD3-driven proliferation 5. FOXL2 and NR5A1 co-expression successfully reprograms human fibroblasts into functional granulosa-like cells with therapeutic potential in polycystic ovary syndrome models 6. FOXL2 and SMAD4 are required for human FSH-β expression in pituitary gonadotropes 7. At the population level, gnomAD v4.1 classifies this gene as LoF-tolerant (LOEUF=1.91); however, 176 ClinVar pathogenic variants demonstrate that clinical pathogenicity in disease contexts is distinct from population-level constraint.