R756G
Category 4 — Stable Fold, Function DisruptedLikely pathogenicLumenal · predictedσ-1 candidateEditorialArginine → Glycine at position 756 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.317 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.71 kcal/mol (destabilising). Charge loss + side-chain loss entirely.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E752 | — | Lost |
| Hydrogen bond | E752 | E752 | Preserved |
| Hydrogen bond | E753 | E753 | Preserved |
| Hydrogen bond | L759 | L759 | Preserved |
| Polar contact | E752 | E752 | Preserved |
| Polar contact | E753 | E753 | Preserved |
| Polar contact | K758 | — | Lost |
| Polar contact | L759 | L759 | Preserved |
| Van der Waals | — | L754 | Gained |
| Van der Waals | K758 | K758 | 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 Likely pathogenic 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
- This rests on a single submitter (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★ single submitter. 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 756 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places R756 within 5 Å of LEU757 (2.5 Å), CYS755 (2.5 Å — potential disulfide site), GLU753 (3.7 Å — likely salt-bridge partner), GLU752 (4.0 Å — second nearby glutamate), and LYS758 (4.4 Å).
The wild-type arginine sits in a charge-rich environment — likely forming a salt bridge with E753 or E752, contributing positive charge to the local electrostatic surface. Replacing R756 with glycine eliminates both the charge and the side chain, leaving a cavity and disrupting the E752/E753 salt-bridge network.
The |ΔΔG| of 0.71 reflects substantial fold cost. AlphaMissense's 0.317 is below threshold — AM under-call. ClinVar Pathogenic + Wolfram 1 confirms clinical pathogenicity.
Druggability Assessment
Mechanism is loss of R756-E752/E753 salt-bridge network. Therapeutic strategy: site-directed at the E752-E753 microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the R756G 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.