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ResearchIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/JCI207160

Gene-specific machine learning model EpiPred identifies likely pathogenic variants in the epilepsy-related gene STXBP1

Jeffrey D. Calhoun,1 Chengbing Wang,2 Carina G. Biar,1 Jonathan R. Gunti,1 John S. Lee,3 Aaron M. Geller,3 Jung H. Hong,1 Santiago Schnell,4 Louis T. Dang,5 Yu Wang,6 Jack M. Parent,6 Lori L. Isom,6 Michael D. Uhler,7 Heather C. Mefford,8 M. Elizabeth Ross,2 Vanessa Aguiar-Pulido,9 and Gemma L. Carvill1

1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

Find articles by Aguiar-Pulido, V. in: PubMed | Google Scholar

1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States of America

3Northwestern IT Research Computing and Data Services, Evanston, United States of America

4Departments of Mathematics, Biochemistry & Cell Biology and Biomedical Data, Dartmouth College, Hanover, United States of America

5Department of Pediatrics, University of Michigan, Ann Arbor, United States of America

6Department of Neurology, University of Michigan, Ann Arbor, United States of America

7Department of Biological Chemistry and Molecular Neuroscience Institute, University of Michigan, Ann Arbor, United States of America

8Center for Pediatric Neurological Disease Research, St. Jude Childen's Research Hospital, Memphis, United States of America

9Department of Computer Science, University of Miami, Miami, United States of America

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Published September 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI207160.
Copyright © 2026, Calhoun et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 17, 2026 - Version history
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Abstract

STXBP1 variants are a frequent cause of early-onset developmental and epileptic encephalopathies and related neurodevelopmental disorders, but the clinical interpretation of these variants remains a major challenge. Most reported STXBP1 missense variants are classified as variants of uncertain significance (VUS), complicating diagnosis, counseling, and patient eligibility for precision therapies. Here, we developed EpiPred, a gene-specific machine learning classifier that predicts the pathogenicity of STXBP1 missense variants and tests these predictions using empirical evidence from well-established cellular assays. Trained on a curated set of pathogenic and benign variants, EpiPred outperformed global prediction tools in accuracy, sensitivity, and specificity. We validated the model’s predictions using variant effect assays that measure protein abundance, solubility, stability, and interaction with the SNARE complex partner syntaxin 1. These biochemical readouts aligned closely with model outputs and enabled reclassification of several possibly misdiagnosed variants, which warrant further validation and clinical reevaluation. We deployed EpiPred in an interactive web application that allows clinicians, researchers, and patients to explore predictions for all possible STXBP1 missense variants. By identifying likely pathogenic STXBP1 variants, including those that may respond to emerging therapies such as protein stabilizers. By coupling gene-calibrated machine learning with orthogonal variant-effect assays and public deployment, EpiPred provides a transferable framework for VUS resolution, trial enrichment, and precision diagnosis across clinically actionable Mendelian disease genes.

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