E462G
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialGlutamate → Glycine at position 462 in a connecting loop. ClinVar Likely pathogenic. AlphaMissense 0.805, DynaMut2 ΔΔG -1.10 kcal/mol (destabilising). Loss of charge plus loss of side chain entirely.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A458 | A458 | Preserved |
| Hydrogen bond | L459 | L459 | Preserved |
| Hydrogen bond | A465 | — | Lost |
| Hydrogen bond | G466 | G466 | Preserved |
| Hydrogen bond | F538 | — | Lost |
| Hydrogen bond | C541 | — | Lost |
| Hydrogen bond | E542 | — | Lost |
| Polar contact | A458 | A458 | Preserved |
| Polar contact | L459 | L459 | Preserved |
| Polar contact | T464 | — | Lost |
| Polar contact | A465 | A465 | Preserved |
| Polar contact | G466 | G466 | Preserved |
| Polar contact | Y534 | — | Lost |
| Polar contact | F538 | — | Lost |
| Polar contact | C541 | — | Lost |
| Van der Waals | T464 | T464 | Preserved |
| Van der Waals | A465 | — | Lost |
| Van der Waals | F538 | — | Lost |
| Hydrophobic | L511 | — | Lost |
| Hydrophobic | F538 | — | Lost |
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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
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.
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 462 sits in a connecting loop. The AlphaFold model places E462 within 5 Å of VAL463 (2.5 Å), THR461 (2.5 Å), LEU459 (3.7 Å), ALA458 (3.8 Å), and THR464 (4.3 Å). The local environment is hydrophobic-leaning with two threonines providing H-bond options.
The wild-type glutamate's carboxylate likely engages T461 or T464 through H-bonding while extending the negative charge toward solvent. Replacing E462 with glycine eliminates both the charge and the side chain — substantial loss for a single substitution.
The |ΔΔG| of 1.10 reflects this. AlphaMissense's 0.805 confirms pathogenic functional consequence. Mechanism is loss of E462's H-bonding role in the loop's polar network plus introduction of backbone flexibility where the wild-type constrained.
Druggability Assessment
Mechanism is loss of E462 H-bonding plus backbone flexibility gain. Therapeutic strategy: site-directed at the loop polar network.
Why this matters
Feed this card to Wolfram Intelligence
Download the E462G 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.