Background: Immune dysregulation, including autoimmunity, autoinflammation, allergy, and malignancy predisposition, adds significant disease burden in primary immune disorders (PID) and inborn errors of immunity (IEIs).

Objective: We evaluated whether the 5-graded immune deficiency and dysregulation activity (IDDA2.1) score, encompassing 21 organ involvement and disease burden parameters, supports diagnosis across a wide spectrum of IEIs.

Methods: From April 2022 to November 2024, collaborators from 84 centers collected 1,043 IDDA score datasets from 825 patients across 89 IEIs (17 disorders with ≥10 patients each; range, 1-196 per IEI), including 177 scores from 141 treated patients. Supervised machine learning models (k-nearest neighbors, support vector machine, logistic regression, random forest) classified patients into disease groups and ranked corresponding predictive features, while unsupervised uniform manifold approximation and projection (UMAP) visualized disease-specific clustering.

Results: Feature analysis reflected clinicians' recognition of IEI patterns and confirmed internal IDDA score consistency. Phenotype profiles in treated patients remained informative, inversely reflecting anticipated treatment-dependent phenotype amelioration. UMAP effectively distinguished IEIs by IDDA2.1 profiles. Genetic disorder prediction achieved 73% overall accuracy, 70% for the correct monogenic IEI, and 93% within the top 3 predictions; classification reached 43% for IEI-International Union of Immunological Society categories and 59% for 12 "cardinal" IEIs (25 genes).

Conclusions: Random forest feature importance analysis can inform targeted clinical screening for key disease manifestations. The top 3 prediction approach demonstrates diagnostic potential, but improved accuracy will require larger, globally shared datasets. Small sample sizes for rare diseases highlight the necessity of broader collaboration to enhance AI-assisted clinical decision-making in the future.