Ca_V1.3 channels are a major class of L-type Ca²⁺ channels which contribute to the rhythmicity of the heart and brain. In the brain, these channels are vital for excitation-transcription coupling, synaptic plasticity, and neuronal firing. Moreover, disruption of Ca_V1.3 function has been associated with several neurological disorders. Here, we focus on the de novo missense mutation A760G which has been linked to autism spectrum disorder (ASD). To explore the role of this mutation in ASD pathogenesis, we examined the effects of A760G on Ca_V1.3 channel gating and regulation. Introduction of the mutation severely diminished the Ca²⁺-dependent inactivation (CDI) of Ca_V1.3 channels, an important feedback system required for Ca²⁺ homeostasis. This reduction in CDI was observed in two major channel splice variants, though to different extents. Using an allosteric model of channel gating, we found that the underlying mechanism of CDI reduction is likely due to enhanced channel opening within the Ca²⁺-inactivated mode. Remarkably, the A760G mutation also caused an opposite increase in voltage-dependent inactivation (VDI), resulting in a multifaceted mechanism underlying ASD. When combined, these regulatory deficits appear to increase the intracellular Ca²⁺ concentration, thus potentially disrupting neuronal development and synapse formation, ultimately leading to ASD.