F783L
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialPhenylalanine → Leucine at position 783 in lumenal domain. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.414 (below threshold), ΔΔG -0.22. pLDDT 61 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | M781 | Gained |
| Hydrogen bond | S785 | S785 | Preserved |
| Polar contact | M781 | M781 | Preserved |
| Polar contact | S785 | S785 | Preserved |
| Hydrophobic | Q667 | Q667 | Preserved |
| Hydrophobic | — | K800 | Gained |
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
- pLDDT 60.84 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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.
Highest in Ashkenazi Jewish: AF 0.064% (19 of 29,598 alleles), 9.3x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Ashkenazi Jewish | 0.064% | 19 / 29,598 | 0 | ~1 in 780 |
| East Asian | 0.022% | 10 / 44,886 | 0 | ~1 in 2240 |
| Remaining individuals | 0.0096% | 6 / 62,472 | 0 | ~1 in 5210 |
| South Asian | 0.0066% | 6 / 91,096 | 0 | ~1 in 7590 |
| European (non-Finnish) | 0.0058% | 69 / 1,180,010 | 0 | ~1 in 8550 |
| African / African American · under-sampled | 0.0013% | 1 / 74,942 | 0 | — |
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 783 in lumenal domain. Neighbors: PRO782 (2.5 Å — partner of G702S neighbor P782), SER784 (2.5 Å), GLN667 (4.4 Å — long-range to Y669 cluster), SER785 (4.7 Å).
F783L removes aromatic. Q667 long-range contact suggests F783 mediates packing between this site and the Y669-C673 cluster. AM 0.414 under-call; WFS1 spectrum does not resolve it (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: lost aromatic + perturbation of long-range Q667 contact. Therapeutic: 783-667 cross-domain.
Why this matters
Feed this card to Wolfram Intelligence
Download the F783L 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.