A Specialized Large Language Model for Clinical Reasoning and Diagnosis in Rare Diseases

W e assemble a large, domain - specialized clinical corpus and a clinician - validated reasoning set, and develop RareSeek - R1 via staged instruction tuning, chain - of - thought learning, and graph - grounded retrieval. Across multicenter EHR narratives and public benchmarks, RareSeek - R1 attains state - of - the - art accuracy, robust generalization, and stability under noisy or overlapping phenotypes. Augmented retrieval yields the largest gains when narratives pair with prioritized variants by resolving ambiguity and aligning candidates to mechanisms. Human studies show performance on par with experienced physicians and consistent gains in assistive use. Notably, transparent reasoning highlights decisive non - phenotypic evidence (median 23.1%, such as imaging, interventions, functional tests) underpinning many correct diagnoses. This work advances a narrative - first, knowledge - integrated reasoning paradigm that shortens the diagnostic odyssey and enables auditable, clinically translatable decision support.