F810L
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialPhenylalanine → Leucine at position 810 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.994 (near-maximum), DynaMut2 ΔΔG +0.08 kcal/mol — essentially neutral. Conservative-looking aromatic-to-aliphatic swap with strong pathogenic signal.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | S807 | S807 | Preserved |
| Hydrogen bond | V813 | V813 | Preserved |
| Hydrogen bond | L814 | L814 | Preserved |
| Hydrogen bond | K843 | — | Lost |
| Hydrogen bond | V861 | — | Lost |
| Polar contact | S807 | S807 | Preserved |
| Polar contact | S808 | S808 | Preserved |
| Polar contact | S812 | S812 | Preserved |
| Polar contact | V813 | V813 | Preserved |
| Polar contact | L814 | L814 | Preserved |
| Polar contact | L842 | — | Lost |
| Van der Waals | S812 | — | Lost |
| Van der Waals | L814 | L814 | Preserved |
| Van der Waals | L842 | — | Lost |
| Van der Waals | — | V861 | Gained |
| Van der Waals | I863 | — | Lost |
| Hydrophobic | A806 | A806 | Preserved |
| Hydrophobic | L814 | L814 | Preserved |
| Hydrophobic | L842 | L842 | Preserved |
| Hydrophobic | I845 | I845 | Preserved |
| Hydrophobic | V861 | V861 | Preserved |
| Hydrophobic | I863 | I863 | Preserved |
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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 810 sits in wolframin's C-terminal lumenal domain near the E809K region (Atlas card adjacent). The AlphaFold model places F810 within 5 Å of GLU809 (2.5 Å — partner of E809K), LYS811 (2.5 Å), SER807 (3.9 Å), SER808 (4.3 Å), and LEU814 (4.5 Å).
Replacing F810 with leucine eliminates the aromatic ring and replaces it with branched aliphatic. The local environment — with E809 and K811 as charged neighbors and multiple serines — was sized around the wild-type aromatic ring. The variant fold accommodates the substitution easily (essentially neutral ΔΔG).
AlphaMissense's 0.994 (near-maximum) confirms severe functional consequence despite the conservative chemistry. The mechanism is loss of the F810 aromatic packing that the wild-type fold depended on for the E809-K811 salt bridge geometry — F810's aromatic ring likely positions E809 and K811 in the productive salt-bridge orientation.
Druggability Assessment
Mechanism is loss of F810 aromatic packing that supported E809-K811 salt-bridge geometry. Therapeutic strategy: same microregion as E809K.
Why this matters
Feed this card to Wolfram Intelligence
Download the F810L 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.