Canonical NOD2 Variant Stratification in Crohn's Disease: A Reproducible Evidence Synthesis for Ileal Phenotype Architecture

In this work, I present a reproducible, hypothesis-driven evidence synthesis evaluating the role of canonical NOD2 variation in shaping ileal-dominant Crohn’s disease architecture. I focus on the three historically validated coding variants p.Arg702Trp (R702W), p.Gly908Arg (G908R), and p.Leu1007fs/3020insC (L1007fs) and integrate population genetics, genotype–phenotype associations, human model availability, and genotype-linked ileal expression data drawn exclusively from public human resources. Rather than claiming new association discovery or directed causality, I assess whether the existing public evidence is sufficiently coherent to justify rigorous testing of a NOD2-centered, ileal-biased causal framework. The analysis demonstrates strong burden-dependent risk scaling, consistent enrichment for ileal and stricturing phenotypes, and the presence of relevant human model systems, while explicitly documenting the limits imposed by summary-level data and underpowered expression cohorts. The result is a transparent, auditable foundation for genotype-stratified mechanistic and translational follow-up in Crohn’s disease.