In Silico Identification and Structural Characterization of High-Risk Missense SNVs in the Human IL23R Gene Relevant to Inflammatory Bowel Disease.

BACKGROUND/

OBJECTIVES

IL23R encodes a pivotal component of the IL-23/Th17 signaling axis and represents a validated genetic susceptibility locus for inflammatory bowel disease (IBD), psoriasis, and ankylosing spondylitis. Despite extensive GWAS data, the functional consequences of the full spectrum of IL23R missense single-nucleotide variants (SNVs) have not been systematically characterized. This study aimed to identify high-risk missense SNVs through a multi-tool in silico pipeline.

METHODS

A total of 723 missense SNVs from NCBI dbSNP were verified against transcript NM_144701.3/Q5VWK5-1 (629 aa) using Ensembl VEP (GRCh38). Sequential filtering was performed using applied SIFT, PolyPhen-2, PROVEAN, E-SNPs&GO, MutPred2, and ConSurf (grade ≥ 7); AlphaMissense and FATHMM-MKL were used as independent annotation layers. Protein stability was assessed with MuPro and DynaMut2 (AlphaFold2 AF-Q5VWK5-F1-v6; pLDDT = 68.19); structural characterization was performed with Project HOPE, and interaction networks were constructed using STRING and GeneMANIA.

RESULTS

Sequential filtering identified 37 high-risk missense variants. MuPro predicted destabilizing effects for 36/37 variants, with concordant DynaMut2 results for 35/37. Project HOPE identified disulfide bond disruption in 11 variants, charge-altering substitutions in 8, and glycine/proline backbone conformational changes in 11. STRING analysis identified IL12RB1 (0.999), IL23A (0.999), JAK2 (0.995), IL12B (0.986), and STAT3 (0.980) as the leading IL23R interactors. The protective variant R381Q was appropriately characterized as neutral by PROVEAN (-1.16) and AlphaMissense (likely_benign), supporting the specificity of the pipeline.

CONCLUSIONS

Comprehensive in silico analysis identified 37 high-risk IL23R missense candidates with convergent computational evidence of predicted deleteriousness, predominantly involving cysteine bridge disruption, charge alteration, and glycine/proline backbone conformational changes. These variants are presented as prioritized candidates for future functional validation and may inform subsequent investigations of IBD susceptibility and IL-23 pathway pharmacogenomics.