Anaplastic lymphoma kinase (ALK) fusion is present in approximately 2-7% of patients with lung adenocarcinoma. ALK fusion-positive patients can benefit from targeted therapy. We herein report a 53-year-old Chinese male patient diagnosed as lung adenocarcinoma with a smoking history. Next-generation sequencing was performed to detect somatic mutations of oncogenic drivers and tumor suppressor genes in plasma-derived circulating tumor DNA using an ultra-deep 160-gene panel. A novel HPCAL1-ALK fusion variant was identified in the patient responding to ALK inhibitor treatments, and the fusion variant was also confirmed by fluorescence in situ hybridization and immunohistochemical. Our study expands the mutational spectrum of ALK fusion variants and provides options for the precise treatment of such patients.