E431Q
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialGlutamate → Glutamine at position 431 inside TM4. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.959, DynaMut2 ΔΔG -0.87 kcal/mol (destabilising). The fifth Atlas variant directly involving E431 — the lumenal-membrane hub residue.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R558 | — | Lost |
| Hydrogen bond | P428 | P428 | Preserved |
| Hydrogen bond | V434 | V434 | Preserved |
| Hydrogen bond | I435 | I435 | Preserved |
| Hydrogen bond | R558 | — | Lost |
| Hydrogen bond | Y563 | Y563 | Preserved |
| Polar contact | P428 | P428 | Preserved |
| Polar contact | C429 | C429 | Preserved |
| Polar contact | A433 | — | Lost |
| Polar contact | V434 | V434 | Preserved |
| Polar contact | I435 | I435 | Preserved |
| Polar contact | R558 | — | Lost |
| Polar contact | A559 | — | Lost |
| Polar contact | Y563 | Y563 | Preserved |
| Van der Waals | C429 | — | Lost |
| Van der Waals | A433 | — | Lost |
| Van der Waals | I435 | — | Lost |
| Van der Waals | A559 | — | Lost |
| Hydrophobic | P428 | P428 | Preserved |
| Hydrophobic | A559 | A559 | Preserved |
| Hydrophobic | Y563 | Y563 | 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
- 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 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 431 is the E431 hub residue itself. The AlphaFold model places E431 within 5 Å of LEU432 (2.4 Å), SER430 (2.5 Å — partner of S430W Atlas card), PRO428 (3.6 Å — partner of P428R Atlas card), ALA559 (3.9 Å — partner of A559D Atlas card), and TYR563 (4.0 Å). The neighbor list reads like a roll call of pathogenic Atlas variants — E431 is in spatial contact with the substituted positions in four other Atlas cards.
Replacing E431 with glutamine eliminates the negative charge at this hub position. The salt bridges and electrostatic contacts that E431 maintained with R558 (across the loop) and with S430's hydroxyl and the lumenal interface lose their negative anchor.
The |ΔΔG| of 0.87 reflects substantial fold cost — E431's role is structurally central. AlphaMissense 0.959 + Wolfram syndrome 1 confirm severe functional consequence.
Druggability Assessment
E431 is the connective hub residue at the lumenal-TM4-connecting loop boundary. The Atlas now contains 5 variants involving E431 (E431Q this card, A559D, P428R, S430W, plus R558C/R558H/A559D microregion). Drug discovery targeting E431 has multi-variant convergence.
Why this matters
Feed this card to Wolfram Intelligence
Download the E431Q 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.