Receptor tyrosine kinases (RTKs) play fundamental roles in human biology and pathology.In the monomeric RTK, the tyrosine kinase domain is repressed by a variety of autoinhibitory mechanisms and possesses low intrinsic kinase activity.Ligand-induced dimerization enables trans-phosphorylation on activation loop (A-loop) tyrosines which releases autoinhibition thus upregulating intrinsic kinase activity.A wealth of structural and biochemical studies have revealed the molecular mechanisms underlying kinase autoinhibition and kinase activation by A-loop tyrosine phosphorylation.However, a fundamental question in RTK signaling has remained unanswered: what precisely determines the intrinsic kinase activity of RTKs? A naturally selected set of pathogenic FGF receptor (FGFR) kinases exhibiting gradations in gain-of-function has afforded us with a unique opportunity to delve into the molecular origin of intrinsic activity of RTKs.Analysis of these pathogenic kinases using a combination of X-ray crystallography, NMR spectroscopy, and kinase assay unveil a "two-state" dynamic equilibrium model for regulation of FGFR kinase, and likely other RTKs, whereby the enzyme toggles between an inhibited ground state and an active state.The pathogenic mutations increase the population of kinase in the active state by introducing intramolecular contacts that enable the kinase to more readily attain and remain longer in the active state.Importantly, the magnitude of intramolecular contacts introduced by the mutations correlate with graded increases in fractional population of kinase in the active state, which in turn correlates with the degree of gain-of-function and the severity of clinical manifestation associated with these mutations.Hence, our data demonstrate that the fractional population of RTKs in the active state determines the intrinsic kinase activity, and provide a blueprint for targeted drug discovery for human skeletal disorders and cancer.