F264L
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorialPhenylalanine → Leucine at position 264 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram-like syndrome. AlphaMissense 0.29 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.19 kcal/mol (stabilising). pLDDT 47 — Category 5 IDR territory.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | S261 | S261 | Preserved |
| Polar contact | S261 | — | Lost |
| Polar contact | S262 | S262 | Preserved |
| Polar contact | — | Q266 | Gained |
| Hydrophobic | I259 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 264 sits in wolframin's N-terminal cytoplasmic domain at the boundary of the IDR. pLDDT of 47 is BELOW the 50 threshold — the Atlas formally classifies this position as Category 5 (IDR exclusion). DynaMut2 predictions in this region are not fully trustworthy.
Neighbors: LEU263 (2.5 Å), LEU265 (2.5 Å), SER261 (4.1 Å). The neighbor sparsity is itself an IDR signature.
AlphaMissense's 0.29 is below threshold. The Conflicting ClinVar classifications and the IDR localization together flag this variant as one where computational drug discovery should pause for wet-lab characterization.
Druggability Assessment
The Atlas routes Category 5 variants to wet-lab characterization rather than computational drug discovery.
Why this matters
Feed this card to Wolfram Intelligence
Download the F264L 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.