W700C
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialTryptophan → Cysteine at position 700 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic (the stronger classification tier). AlphaMissense 0.999, DynaMut2 ΔΔG -0.10 kcal/mol — essentially no destabilization. A pathogenic variant where the fold cost is negligible: the damage is mechanistic, not structural.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L664 | — | Lost |
| Hydrogen bond | — | W666 | Gained |
| Hydrogen bond | E824 | E824 | Preserved |
| Hydrogen bond | F825 | F825 | Preserved |
| Polar contact | L664 | — | Lost |
| Polar contact | E824 | E824 | Preserved |
| Polar contact | F825 | F825 | Preserved |
| Aromatic / π | W666 | — | Lost |
| Aromatic / π | Y669 | — | Lost |
| Hydrophobic | W666 | — | Lost |
| Hydrophobic | Y669 | — | Lost |
| Hydrophobic | V698 | — | Lost |
| Hydrophobic | M781 | M781 | Preserved |
| Hydrophobic | I802 | — | Lost |
| Hydrophobic | F825 | F825 | Preserved |
| Hydrophobic | L829 | — | Lost |
| Hydrophobic | F840 | — | 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
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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as 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 700 sits in wolframin's C-terminal lumenal domain (residues 653–869). In the AlphaFold model, W700 is packed against immediate sequence neighbors THR699 (2.5 Å) and THR701 (2.4 Å), and into a distant aromatic-hydrophobic pocket containing PHE825 (3.9 Å) and MET781 (4.8 Å). The wild-type indole ring contributes π-stacking to PHE825 and hydrophobic contact to MET781 — substantial packing density into a defined local environment.
Replacing tryptophan with cysteine here removes the bulky aromatic indole entirely and replaces it with a small thiol. The volume difference is large — roughly 100 ų — but the resulting cavity is partially filled by the surrounding atoms relaxing slightly, and the new free thiol does not introduce charge or strong polarity. This explains the surprisingly small |ΔΔG| of 0.10 kcal/mol: DynaMut2 reports the fold is essentially unperturbed.
The contrast with W700S (same position, serine substitution) is the structural lesson. W700S has |ΔΔG| of 2.49 kcal/mol — Category 2, moderately destabilizing — because the polar hydroxyl introduces unfavorable contacts in the hydrophobic pocket. W700C, with a thiol instead of a hydroxyl, sits closer to the chemistry the pocket can tolerate. Yet both are pathogenic, with W700C carrying the stronger 'Pathogenic' ClinVar classification.
The inference: W700's pathogenic mechanism is not primarily structural destabilization. The lost interaction — likely the π-stacking with PHE825 — is functional rather than fold-critical. The indole at W700 probably mediates a specific protein-protein interaction surface or a fold-locking contact whose loss is functionally severe even when the fold itself remains intact. Additionally, the newly introduced free thiol in the ER lumen's oxidative environment may form aberrant disulfide bonds with nearby cysteines (such as C673 or C690 in the same domain), introducing a misfolding pressure that DynaMut2's predicted ΔΔG cannot fully capture.
Druggability Assessment
The mechanism is the loss of a specific functional interaction — likely the π-stacking surface between W700 and PHE825 — plus the introduction of a free thiol that may participate in aberrant disulfide formation in the oxidative ER lumen. Neither mechanism collapses the fold; both produce severe functional consequence.
The therapeutic strategy is site-directed small-molecule design that either re-creates the lost W700-PHE825 contact (via an aromatic small molecule that occupies the pocket) or blocks the aberrant cysteine disulfide chemistry (via a thiol-protective small molecule). The cleanest druggability profile in the Atlas: maximum pathogenicity, minimum fold disruption, defined target geometry.
Why this matters
Feed this card to Wolfram Intelligence
Download the W700C 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.