An Arg457Gln variant in the CREBRF gene (encoding for Cyclic AMP Response Element Binding Protein 3 Regulatory Factor) has previously been identified as driving excess body weight in numerous Pacific/Oceanic populations. Intriguingly, despite the substantial increase in body mass, carriers of the Arg457Gln variant had a paradoxical reduction in their risk for type 2 diabetes, indicating that this gene has a critical role in whole-body metabolism. To study the function of this variant in more detail, we have generated mice on an FVB background where this CREBRF Arg457Gln variant has been knocked in to replace the endogenous CREBRF. Characterisation of the whole-body phenotype for male and female mice on a regular chow diet was followed by analyses of the male transcriptomic and molecular signalling pathways. Regular assessment of body composition found that both lean mass and naso-anal length were significantly increased by the CREBRF variant in male mice, but unaltered by genotype in females. RNA-seq analysis performed on male liver and muscle tissue revealed genotype-dependent differential expression of genes contributing to pathways involving protein synthesis, cholesterol metabolism, stress response, and cellular respiration. Alterations to molecular signalling pathways were further examined via protein expression analysis. Overall, this novel mouse model appears to show a whole-body growth phenotype effect of the CREBRF variant in males, partially underscored by alterations to the transcriptome. This phenotype was driven by lean mass rather than adiposity, perhaps inviting reconsideration of the precise association between increased body mass and obesity risk in variant allele carriers.