We demonstrate here that the novel mutations Ile1102Thr and His1086Leu (identified in HPRCC and affecting the N‐lobe) cause, in the absence of HGF, only minor focus formation in NIH3T3 cell cultures and are unable to promote epithelial cell motility and downstream pathway activation, whereas HGF stimulation increases focus formation, promotes cell migration, and strongly activates the RAS–ERK and PI3K‐AKT signaling pathways. The gene discussed is HGF; the disease is papillary renal cell carcinoma.