G107E
Category 3/4 — Most DruggableLikely pathogenicCytoplasmic · predictedEditorialGlycine → Glutamate at position 107 in wolframin's N-terminal cytoplasmic domain. ClinVar Likely pathogenic, associated with classical autosomal recessive Wolfram syndrome 1. AlphaMissense 0.993, DynaMut2 ΔΔG -1.51 kcal/mol (destabilising). The Atlas's strongest N-terminal cytoplasmic variant — a region where most pathogenic variants until now have not had structural characterization.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Q103 | Q103 | Preserved |
| Hydrogen bond | — | T104 | Gained |
| Hydrogen bond | L111 | L111 | Preserved |
| Hydrogen bond | — | L130 | Gained |
| Polar contact | Q103 | Q103 | Preserved |
| Polar contact | T104 | T104 | Preserved |
| Polar contact | E105 | E105 | Preserved |
| Polar contact | Y110 | — | Lost |
| Polar contact | L111 | L111 | Preserved |
| Polar contact | A126 | A126 | Preserved |
| Polar contact | — | L130 | Gained |
| Polar contact | — | A133 | Gained |
| Polar contact | — | A141 | Gained |
| Van der Waals | — | Q103 | Gained |
| Van der Waals | — | T104 | Gained |
| Van der Waals | E105 | E105 | Preserved |
| Van der Waals | — | L111 | Gained |
| Van der Waals | — | A126 | Gained |
| Van der Waals | — | W129 | Gained |
| Van der Waals | — | L130 | Gained |
| Hydrophobic | — | T104 | Gained |
| Hydrophobic | — | W129 | Gained |
| Hydrophobic | — | L130 | 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
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 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.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
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. |
|---|---|---|---|---|
| Middle Eastern · under-sampled | 0.017% | 1 / 5,750 | 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 107 sits in wolframin's N-terminal cytoplasmic domain, the region facing the cytosol where the protein engages cytosolic regulatory partners. The AlphaFold model places G107 within 5 Å of VAL106 (2.5 Å), LYS108 (2.5 Å), THR104 (3.7 Å), GLN103 (3.8 Å), TRP129 (4.0 Å — a longer-range contact), and ALA126 (4.0 Å). The local environment is mixed polar-hydrophobic, consistent with a cytosolic protein surface.
The wild-type glycine at 107 is structurally meaningful — glycine is the only amino acid with no side chain, which allows backbone conformations (especially in the Ramachandran 'left-handed helix' region) that other amino acids cannot adopt. Glycines in specific positions enable backbone flexibility that other residues constrain. Position 107's glycine, sitting between V106 and K108 and contacting TRP129 across a structural element, plausibly provides exactly this flexibility — allowing the local backbone to adopt a configuration that other amino acids cannot.
Replacing glycine with glutamate has two layered structural costs. First, the backbone is now constrained by the glutamate side chain's steric requirements — the local conformation cannot adopt the wild-type glycine geometry. Second, the introduced carboxylate adds negative charge to a position where the wild-type contributed none. Combined, these produce a |ΔΔG| of 1.51 kcal/mol — substantial for a cytosolic position, reflecting both the lost backbone flexibility and the steric-plus-electrostatic accommodation needed.
AlphaMissense's 0.993 score reflects the high pathogenic potential of removing a structurally critical glycine. The variant is one of the few in this batch where both the structural cost (relatively high |ΔΔG|) and the functional cost (high AM) are clearly visible — a coherent Category 3/4 signature.
Druggability Assessment
The mechanism is loss of backbone flexibility (the wild-type glycine enabled a backbone conformation the mutant glutamate cannot) plus the addition of negative charge into a structurally constrained position. The therapeutic strategy is site-directed: a small molecule that stabilizes the local fold against the variant's preferred (and incorrect) conformation, biasing the population toward functional protein.
This is one of the few N-terminal cytoplasmic variants in the Windsor Set with full atlas characterization. Most pathogenic N-terminal variants in WFS1 have not had structural analysis at this resolution. The atlas brings that resolution to the cytosolic domain for the first time.
Why this matters
Feed this card to Wolfram Intelligence
Download the G107E 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.