The calcium-sensing receptor (CaSR) is a G-protein coupled receptor (GPCR) that maintains systemic calcium homeostasis by detecting alterations in extracellular calcium, which it transduces into signalling changes, mainly via the Gq/11 pathway, leading to a decrease in PTH secretion. The importance of CaSR is highlighted by studies of patients that harbour germline CaSR mutations, which lead to a gain of receptor function in autosomal dominant hypocalcemia (ADH), and a loss-of-function, in familial hypocalciuric hypercalcemia (FHH). Similarly, mutations in GNA11, which encodes the G-protein alpha-11 subunit (Gα11), have been found to cause ADH type-2 (ADH2) and FHH type-2 (FHH2). We hypothesised that additional rare coding GNA11 variants may influence Gα11 functional activity and aimed to identify previously uncharacterised, non-synonymous, germline GNA11 variants using online databases of large-scale sequencing projects, including the Exome Variant Server and 1000Genomes, comprising exomes from 69,713 unrelated individuals. We identified 61 missense GNA11 variants, and selected those likely to be pathogenic for further study, based on a criteria of: a very low population frequency (0.000014); evolutionary conservation amongst orthologs and paralogs; and predicted severity on protein composition (using SIFT and polyphen-2). Using these criteria, we identified 9 variants for further analysis by three-dimensional homology modelling based on Gαq, Gαs and Gαi structures. We found 3 variants (G51R, G66D, A231T) located at the interdomain interface, predicted to disrupt GDP binding; 3 variants (R147C, Q152H, D243G) located close to the Gα11 switch 3 region, predicted to affect GDP-GTP exchange; 1 variant (R213W) located at the Gα-Gβγ and Gα-PLC interaction site; and 2 variants (N336S, R338C) located within the α5-helix that binds GPCR transmembrane domains and intracellular loops, predicted to disrupt GPCR-G-protein interaction. Thus, we have identified residues that may be important for Gα11 structure-function activity, and further in vitro investigation is required to elucidate their effects on CaSR signalling.