The roles of auxiliary α2δ subunits of voltage-gated calcium channels (CaVs) in modulating channel membrane expression and calcium current properties are widely recognized. In addition, recent literature suggests an important role of α2δ proteins in synapse formation, differentiation, and synaptic wiring. Therefore, it is not surprising that α2δ proteins have been linked to neurological, neurodevelopmental, and neuropsychiatric disorders. Genetic variants of the α2δ-2 isoform have been associated with epileptic encephalopathy and cerebellar atrophy. In this study we performed a detailed functional characterization of a previously reported homozygous mutation (p.R593P, R596P in mouse cDNA) found in two siblings with severe epileptic encephalopathy. In contrast to previous studies, we analysed potential consequences on both, calcium channel-dependent as well as channel-independent synaptic functions of α2δ-2. Our data show that the R596P mutation drastically decreases membrane expression and synaptic targeting of α2δ-2. Upon heterologous co-expression, this defect correlates with altered biophysical properties of postsynaptic CaV1.3 channels but has no effect on presynaptic CaV2.1 channels. Overexpression of α2δ‑2_R596P in mouse hippocampal neurons disrupts the ability of α2δ-2 to increase presynaptic abundance of endogenous CaV2.1 channels and presynaptic calcium transients. Importantly, our data also demonstrate that the R596P mutation reduces 1) trans-synaptic recruitment of GABAA receptors, 2) presynaptic synapsin clustering in glutamatergic synapses, and 3) amplitudes of glutamatergic mEPSCs, which, altogether, indicate a disrupted synaptic differentiation. Taken together, our data strongly link the human R593P mutation to the underlying neurodevelopmental disorder and highlight the importance in defining α2δ-related disorders as both, ‘‘channelopathies’’ and “synaptopathies”.