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This study presents a multi-faceted approach combining stereotactic biopsy with standard clinical open-craniotomy for sample collection, voxel-wise analysis of MR images, regression-based Generalized Additive Models (GAM), & whole-exome sequencing. This work aims to demonstrate the potential of machine learning algorithms to predict variations in cellular & molecular tumor characteristics. This retrospective study enrolled ten treatment-naive patients with radiologically confirmed glioma (5 WHO grade II, 5 WHO grade IV). Each patient underwent a multiparametric MR scan (T1W, T1W-CE, T2W, T2W-FLAIR, DWI) prior to surgery (27.9+/-34.0 days). During standard craniotomy procedure, at least 1 stereotactic biopsy was collected from each patient, with screenshots of the sample locations saved for spatial registration to pre-surgical MR data. Whole-exome sequencing was performed on flash-frozen tumor samples, prioritizing the signatures of five glioma-related genes: IDH1, TP53, EGFR, PIK3CA, & NF1. Regression was implemented with a GAM using a univariate shape function for each predictor. Standard receiver operating characteristic analyses were used to evaluate detection, with AUC (area under curve) calculated for each gene target & MR contrast combination. The mean AUC for the five gene targets & 31 MR contrast combinations was 0.75+/-0.11; individual AUCs were as high as 0.96 for both IDH1 & TP53 with T2W-FLAIR & ADC & 0.99 for EGFR with T2W & ADC. An average AUC of 0.85 across the five mutations was achieved using the combination of T1W, T2W-FLAIR, & ADC. These results suggest the possibility of predicting exome-wide mutation events from non-invasive, in vivo imaging by combining stereotactic localization of glioma samples & a semi-parametric deep learning method. This approach holds potential for refining targeted therapy by better addressing the genomic heterogeneity of glioma tumors., Comment: Keywords: multiparametric MRI, intra-tumoral heterogeneity, machine learning, brain tumor, stereotactic biopsy. Note: A portion of this study was presented as a talk in RSNA (Radiological Society of North America) 2021 and was awarded the RSNA Chynn Award for Neuroradiology Research