GNA14 encodes a G protein alpha subunit that functions as a guanine nucleotide-binding protein involved in transmembrane signaling. 1 It acts as a molecular transducer downstream of G protein-coupled receptors, modulating phospholipase C and other signaling cascades. 2 Mechanistically, GNA14 participates in vascular development and angiogenesis pathways. 3 The protein localizes to both cytoplasm and nucleus in endothelial and smooth muscle cells, where it regulates signaling outcomes. 3 In hepatocellular carcinoma, GNA14 interacts with RACK1 to suppress MAPK/JNK and PI3K/AKT signaling, and its expression is epigenetically downregulated through promoter hypermethylation by HBV-encoded X protein. 24 Clinically, GNA14 mutations are prominent in vascular neoplasms. Somatic missense mutations (particularly p.Gln205Leu) drive extra-axial cavernous hemangiomas through MAPK and angiogenesis pathway upregulation. 5 GNA14 mutations are present in ~82% of cherry hemangiomas, making it the most commonly mutated gene in vascular tumors. 6 GNA14 is identified as the most frequent somatic variant in hepatic small vessel neoplasms (75% of cases). 7 Conversely, in hepatocellular carcinoma, GNA14 acts as a tumor suppressor; low expression correlates with aggressive disease and poor survival. 24 These contrasting roles suggest GNA14 has context-dependent functions in tumorigenesis.