What question did this study set out to answer?

This work aims to enhance the detection of pathogenic genetic variants using 3D simulation methods.

March 6, 2026Open Access

ARCHCODE: 3D Chromatin Loop Extrusion Simulation Reveals Enhancer-Proximal Structural Pathogenicity Across Nine Genomic Loci

Key Points

This work aims to enhance the detection of pathogenic genetic variants using 3D simulation methods.
Analyzed 30,318 ClinVar variants across 9 genomic loci
Utilized ARCHCODE for 3D enhancer-promoter contact detection
Validated findings with Hi-C data and conducted RNA-seq analysis
Identified 27 pearl variants undetected by traditional tools
Achieved a correlation coefficient of r=0.28-0.59 with Hi-C validation
Demonstrated a 2.8x increase in RNA-seq sensitivity with p<0.0001

Abstract

30,318 ClinVar variants across 9 loci. 27 pearl variants invisible to VEP (0), SpliceAI (0.00), CADD (15.7), MPRA (null), gnomAD (85% AF=0) — only ARCHCODE detects via 3D enhancer-promoter contact. Hi-C validation r=0.28-0.59. AlphaGenome multimodal: 2.8x RNA-seq (p<0.0001). Version 2.9 (gnomAD population analysis added). Code: https://github.com/sergeeey/ARCHCODE

ARCHCODE: 3D Chromatin Loop Extrusion Simulation Reveals Enhancer-Proximal Structural Pathogenicity Across Nine Genomic Loci

Key Points

Abstract

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