L842F
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialLeucine → Phenylalanine at position 842 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.956, DynaMut2 ΔΔG -0.61 kcal/mol (destabilising). Volume increase variant near the L829 region.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R805 | R805 | Preserved |
| Hydrogen bond | — | S826 | Gained |
| Hydrogen bond | — | A844 | Gained |
| Polar contact | R805 | R805 | Preserved |
| Polar contact | F810 | F810 | Preserved |
| Polar contact | A844 | A844 | Preserved |
| Aromatic / π | — | F810 | Gained |
| Van der Waals | F810 | F810 | Preserved |
| Van der Waals | — | A844 | Gained |
| Hydrophobic | I777 | I777 | Preserved |
| Hydrophobic | L804 | L804 | Preserved |
| Hydrophobic | A806 | A806 | Preserved |
| Hydrophobic | F810 | F810 | Preserved |
| Hydrophobic | — | L814 | Gained |
| Hydrophobic | F825 | — | Lost |
| Hydrophobic | I845 | I845 | 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00025% (3 of 1,179,700 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00025% | 3 / 1,179,700 | 0 | ~1 in 196620 |
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 842 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L842 within 5 Å of GLU841 (2.5 Å), LYS843 (2.5 Å — same K843 as the K862-K843 cluster), ARG805 (3.7 Å — long-range, near A806P), SER826 (4.2 Å), and ALA844 (4.7 Å).
The wild-type leucine fits cleanly into this mixed polar-basic environment. Replacing it with phenylalanine adds aromatic volume that the local pocket was not sized for. The K843 + L842 + R805 region is reorganized.
The |ΔΔG| of 0.61 reflects modest fold cost. AlphaMissense's 0.956 confirms severe functional consequence. The proximity to A806P (3.7 Å through R805) and the K843 contact suggest this region is a multi-variant hub.
Druggability Assessment
Mechanism is volume mismatch in the E841-L842-K843-R805 polar-basic environment. Therapeutic strategy: site-directed at this microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the L842F 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.