V536E
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialValine → Glutamate at position 536 inside wolframin's seventh transmembrane helix (TM7). ClinVar carries conflicting classifications. AlphaMissense 0.980, DynaMut2 ΔΔG -1.62 kcal/mol (destabilising). A charge-into-membrane variant with a stronger structural cost than the typical TM-helix substitution.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | Y405 | Gained |
| Hydrogen bond | V532 | V532 | Preserved |
| Hydrogen bond | P533 | P533 | Preserved |
| Hydrogen bond | W540 | W540 | Preserved |
| Polar contact | — | Y405 | Gained |
| Polar contact | — | F408 | Gained |
| Polar contact | V532 | V532 | Preserved |
| Polar contact | P533 | P533 | Preserved |
| Polar contact | Y534 | Y534 | Preserved |
| Polar contact | M539 | — | Lost |
| Polar contact | W540 | W540 | Preserved |
| Van der Waals | — | Y405 | Gained |
| Van der Waals | — | F408 | Gained |
| Van der Waals | — | P533 | Gained |
| Hydrophobic | T361 | — | Lost |
| Hydrophobic | Y405 | Y405 | Preserved |
| Hydrophobic | F408 | F408 | 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 Conflicting classifications of pathogenicity 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
- 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.
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 536 sits in the middle of TM7. The AlphaFold model places V536 within 5 Å of CYS537 (2.5 Å), LEU535 (2.5 Å), PHE408 (3.7 Å, from TM3 — TM3-TM7 cross-helix contact), PRO533 (3.8 Å), TYR534 (4.2 Å), and VAL532 (4.3 Å). The wild-type valine's small branched hydrophobic side chain packs into a hydrophobic environment dominated by aromatic and aliphatic residues, including the cross-helix contact to PHE408 in TM3.
Replacing valine with glutamate at this position is energetically costly. Glutamate's carboxylate group is negatively charged at physiological pH; carrying that charge into the bilayer hydrophobic core requires significant local rearrangement to position the charge near water or polar headgroups. The side chain volume is also larger than valine's, so even before considering electrostatics the local packing has to accommodate more mass.
DynaMut2 returns |ΔΔG| = 1.62 kcal/mol — the highest in this batch and approaching the Category 2 threshold (|ΔΔG| ≥ 2). The fold survives, but the energetic cost is substantial. The TM3-TM7 cross-helix interface at the PHE408 contact is particularly affected: the carboxylate's polarity is incompatible with the aromatic-hydrophobic packing the wild-type maintained.
The conflicting ClinVar classifications likely reflect the variant's mechanism-dependent functional consequence. In one cellular context (e.g., heterozygous expression where the partner allele compensates) the variant may produce mild phenotype; in homozygous or compound-heterozygous context it likely produces full Wolfram syndrome 1. AlphaMissense's score of 0.980 reflects the variant's high pathogenic potential when context allows.
Druggability Assessment
The mechanism is charge-into-membrane disruption at the TM3-TM7 cross-helix interface (PHE408 at 3.7 Å). The introduced carboxylate is incompatible with the hydrophobic packing the wild-type valine maintained, and the helix-helix register is perturbed.
Therapeutic strategy: a small molecule that stabilizes the TM3-TM7 interface at the PHE408/V536 contact. Alternative: a pharmacological chaperone that biases the fold against the variant's locally rearranged geometry. The closer-to-Cat-2 |ΔΔG| suggests chaperone screening may be a more accessible approach than purely site-directed binders.
Why this matters
Feed this card to Wolfram Intelligence
Download the V536E 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.