E394V
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialGlutamate → Valine at position 394 in a connecting loop. ClinVar Conflicting including spastic ataxia and DFNA6. AlphaMissense 0.917, ΔΔG +1.18 STABILISING.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R375 | — | Lost |
| Ionic bond | R522 | — | Lost |
| Hydrogen bond | R375 | — | Lost |
| Hydrogen bond | V390 | V390 | Preserved |
| Hydrogen bond | E391 | E391 | Preserved |
| Hydrogen bond | F397 | F397 | Preserved |
| Hydrogen bond | G398 | G398 | Preserved |
| Hydrogen bond | R522 | — | Lost |
| Polar contact | R375 | — | Lost |
| Polar contact | V390 | V390 | Preserved |
| Polar contact | E391 | E391 | Preserved |
| Polar contact | F397 | F397 | Preserved |
| Polar contact | G398 | G398 | Preserved |
| Polar contact | R522 | — | Lost |
| Van der Waals | W371 | — | Lost |
| Hydrophobic | W371 | W371 | Preserved |
| Hydrophobic | F374 | F374 | Preserved |
| Hydrophobic | V390 | V390 | 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
Observed in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Ataxia / spastic ataxia (inheritance not specified); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Ataxia / spastic ataxiainheritance not specifiedsubmitted as: Spastic ataxia
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: 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
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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 European (non-Finnish): AF 0.016% (190 of 1,180,010 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.016% | 190 / 1,180,010 | 0 | ~1 in 3110 |
| Admixed American | 0.015% | 9 / 59,864 | 0 | ~1 in 3330 |
| Remaining individuals | 0.0080% | 5 / 62,482 | 0 | ~1 in 6250 |
| Finnish | 0.0047% | 3 / 64,032 | 0 | ~1 in 10670 |
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 394 sits in a connecting loop. Neighbors: VAL395 (2.5 Å), ALA393 (2.5 Å), VAL390 (3.8 Å), GLU391 (3.8 Å — second nearby glutamate).
The wild-type E394 with nearby E391 forms a charge cluster in this loop. Replacing E394 with valine eliminates one of two negative charges; the variant fold packs more efficiently with valine in the surrounding hydrophobic environment (V395, V390, A393), producing stabilising ΔΔG of +1.18.
Yet AlphaMissense 0.917 + spastic ataxia + DFNA6 clinical evidence confirm severe consequence. The mechanism is loss of the negatively-charged surface that the wild-type E394 contributed to — partner-recognition disruption despite structural gain.
Druggability Assessment
Mechanism: loss of E394 charge from the local surface patch. Therapeutic: recognition-surface site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the E394V 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.