It is increasingly evident that non-coding sequence variation plays a major role in controlling gene expression and consequently influencing disease susceptibility. One of the greatest challenges currently facing genetics is determining which genetic variants have a functional effect on gene expression rather than being neutral. We have utilised a general statistical genetic framework for assessing the likely functional status of genetic variants. For each sequence variant a posterior probability of effect can be used to prioritize additional molecular experiments that probe for function. Current ‘gold standard’ approaches for assessing whether a variant is functional are, firstly the reporter gene assay to assess allelic differences in transcriptional activity, and secondly the electrophoretic mobility shift assay to assess allelic differences in transcription factor binding. Although useful, these assays have inherent limitations including the fact that they generate in vitro measures of function and lack cell or tissue-specific context including endogenous chromatin context. Here we present the development of two novel approaches to assessing SNP functionality using whole-genome functional assays that we have recently validated. By combining statistical prioritisation, ‘gold standard’ assays and our in vivo genome-wide assays of function, we are able to greatly increase the confidence in which single nucleotide variants are assigned functional relevance.