Slow-channel congenital myasthenic syndromes (CMS) caused by mutations in subunits of the endplate ACh receptor (AChR) result in prolonged synaptic currents and excitotoxic injury of the postsynaptic region by Ca²⁺ overloading. The Ca²⁺ overloading could owe entirely to the prolonged openings of the AChR channel or could be abetted by enhanced Ca²⁺ permeability of the mutant channels. We therefore measured the fractional Ca²⁺ current (P_f ), defined as the percentage of the total ACh-evoked current carried by Ca²⁺ ions, for AChRs harboring the G153S or the V249F slow-channel mutation, and for wild-type human AChR whose P_f has not yet been determined. Experiments were performed in transiently transfected GH4C1 cells and human myotubes with simultaneous recording of ACh-evoked whole-cell currents and fura-2 fluorescence-signals. We found that the P_f of the wild-type human endplate AChR was unexpectedly high (P_f ~7%), but neither the V249F nor the G153S mutation altered P_f . Fetal human AChRs containing either the wild type or the mutated subunit had a much lower P_f (2 to 3 %). We conclude that the Ca²⁺ permeability of human endplate AChR is higher than that reported for any other human nicotinic AChR, with exception of 7-containing AChRs (Pf >10 %); and that neither the G153S nor the V249F mutations affect the P_f of fetal or adult endplate AChRs. However, the intrinsically high Ca²⁺ permeability of human receptor likely predisposes to development of the endplate myopathy when opening events of the AChR channel are prolonged by altered AChR-channel kinetics.