AHNAK2 is a large nucleoprotein (>600 kDa) with ~90% sequence homology to AHNAK, localized to the plasma membrane, cytosol, cytoplasm, nucleus, and sarcolemma 1. It functions in calcium channel modulation and membrane repair 1, with evidence of involvement in calcium signaling 2. Mechanistically, AHNAK2 regulates multiple oncogenic signaling pathways including AKT/GSK-3β, PI3K/AKT, ERK, MAPK, and Wnt, while promoting epithelial-mesenchymal transition (EMT) and cancer stemness 134. In ccRCC, hypoxia-inducible factor-1α (HIF1α) drives AHNAK2 upregulation, enhancing tumor progression 5. In pancreatic cancer, cytoplasmic AHNAK2 colocalizes with Cortactin at filopodia to enhance cellular invasion 6. ABNORMAL EXPRESSION is associated with multiple malignancies. In colorectal cancer, elevated AHNAK2 confers 5-fluorouracil resistance via AKT/GSK-3β activation 3. In thyroid and renal cell carcinomas, upregulation correlates with aggressive clinicopathological features, poor prognosis, and shorter recurrence-free survival 754. AHNAK2 plasma levels show diagnostic potential for pancreatic cancer (83.33% specificity, 86.67% sensitivity at 421.47 ng/ml) 6. Genetically, AHNAK2 appears as a candidate gene for neurodevelopmental disorders; compound heterozygous missense variants were identified in a patient with cardio-facio-cutaneous-like phenotype 28.