Given the evidence that the TBC1D1 R125W variant is associated with familial extreme obesity but does not appear to be associated with obesity in general population cohorts [5], [6] together with the physiological relevance of TBC1D1 in regulating glucose and lipid homeostasis, we set out both to (i) model the location of R125 in the first PTB domain of TBC1D1 and (ii) undertake a further study of the familial association of the R125W variant with obesity in a general population birth cohort of 2,292 white British mother-offspring pairs. The gene discussed is PTBP1; the disease is Obesity.