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P216R
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorialProline → Arginine at position 216 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)
Proline → Arginine at position 216 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes, Cataract 41, Wolfram. AlphaMissense 0.11 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.20. pLDDT 41 — Category 5 IDR!
Interactive 3D Structure
Wild-type reference
Wild-type P216 — native residue, no strong sidechain contacts
DynaMut2 mutant · P216R
Mutant R216 — energy-minimized; local contact network preserved
Computational Predictions
DynaMut2 ΔΔG
0.20kcal/mol
Stabilising — mild
AlphaMissense
0.105
LBen
AlphaFold pLDDT
41
model confidence
Schema
Cat 5
Category 5 — IDR Exclusion
Clinical Evidence
ClinVar classificationConflicting classifications of pathogenicity
Review statuscriteria provided, conflicting classifications
Associated conditionsMonogenic diabetes; Cataract 41; Wolfram syndrome 1
InheritanceMulti-phenotype.
Population frequency (gnomAD v4)Ultra-rare · AF 0.0063%
cDNA changec.647C>G
ClinVar accessionVCV000393386
Last evaluated2025/12/20 00:00
Observed at very low frequency in gnomAD.
Structural Context
Position 216 at pLDDT 41 — DEEP IDR. Sparse neighbors (GLY217, GLN215, ALA214). DynaMut2 untrustworthy.
P216R introduces charge + removes backbone constraint in disordered region. AM 0.11 under-call; multi-phenotype confirms clinical pathogenicity.
Amino-acid chemistry
Proline (P) → Arginine (R) — rigid helix-breaking replaced by long positively-charged amine.
Position in the protein
N-terminal cytoplasmic domain · position 216 IDR (pLDDT 41 — deep IDR).
Druggability Assessment
Category 5 — IDR Exclusion. pLDDT 41 deep IDR. AlphaMissense 0.11 below threshold. DynaMut2 prediction not trustworthy.
The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity.
The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity.
Why this matters
P216R is another deep-IDR variant in this batch — Atlas appropriately flags for wet-lab.
Therapeutic Strategy Handoff · prediction
Feed this card to Wolfram Intelligence
Download the P216R PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.
Download P216R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.
UniProt Domain Annotation
Chain1–890 · Wolframin
Region1–321 · Interaction with ATP6V1A