Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of disorders characterised by early onset, lean, non-autoimmunity mediated, non-insulin-dependent diabetes often with autosomal-dominant inheritance and specific pharmaco-genetic response. We describe two siblings with HNF1A-MODY (MODY3) due to a novel germline variant p.(His126Asp) which segregates with diabetes in the family. However, contrary to anticipated therapeutic response, blood glucose in this sib-pair did not respond to sulphonylureas (both low and high dose), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), and glucagon-like peptide-1 receptor agonists (GLP-1RA), also known as incretin mimetics. The unexpected limited pharmaco-therapeutic response could potentially be unique to this specific variant and/or progressive pancreatic β-cell failure associated with long-standing disease duration, higher BMI and glucose-toxicity. Therefore, we report a novel-variant MODY3 sib-pair with atypical pharmaco-therapeutic response i.e. resistant to multiple anti-diabetes agents namely sulphonylurea, DPP-4 inhibitors and GLP-1RA treatment.