Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN ( = 237), painless-DPN ( = 309), painful-SFN ( = 547) and painless-SFN ( = 32), recruited in four different centers, were analyzed for and variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of and revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, = 194/1125). A potential pathogenic variant was present in 18.1% ( = 142/784) of painful neuropathy patients vs. 15.2% ( = 52/341) of painless neuropathy patients (17.3% ( = 41/237) for painful-DPN patients, 14.9% ( = 46/309) for painless-DPN patients, 18.5% ( = 101/547) for painful-SFN patients, and 18.8% ( = 6/32) for painless-SFN patients). Of the variants detected, 70% were in and . The frequency of and variants was the highest in painful-SFN patients, variants in painful-DPN patients, and variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.