W700S
Category 2 — Moderately DestabilizingLikely pathogenicLumenal · predictedσ-1 candidateEditorialTryptophan → Serine at position 700 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.996 (deeply pathogenic), DynaMut2 ΔΔG -2.49 kcal/mol (destabilising). Together with V779G, the second of only two Cat 2 variants in the entire 245-variant Atlas.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L664 | — | Lost |
| Hydrogen bond | E824 | E824 | Preserved |
| Hydrogen bond | F825 | F825 | Preserved |
| Polar contact | L664 | — | Lost |
| Polar contact | E824 | — | Lost |
| Polar contact | F825 | F825 | Preserved |
| Aromatic / π | W666 | — | Lost |
| Aromatic / π | Y669 | — | Lost |
| Van der Waals | — | F825 | Gained |
| Hydrophobic | W666 | — | Lost |
| Hydrophobic | Y669 | — | Lost |
| Hydrophobic | V698 | — | Lost |
| Hydrophobic | M781 | — | Lost |
| Hydrophobic | I802 | — | Lost |
| Hydrophobic | F825 | — | Lost |
| 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 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 700 sits in wolframin's C-terminal lumenal domain (residues 653–869), the protein's largest soluble region and the documented site of partner interactions with ATF6 (the master regulator of the unfolded protein response) and the Na+/K+ ATPase β1 subunit. The AlphaFold model shows W700 packed against immediate sequence neighbors THR699 (2.5 Å) and THR701 (2.4 Å), and into a distant hydrophobic pocket containing PHE825 (3.9 Å) and MET781 (4.8 Å). The aromatic indole ring of tryptophan provides a substantial hydrophobic contact surface against PHE825 — likely a π-stacking or edge-face aromatic interaction — and into the lipid-like pocket lined by methionine.
Replacing tryptophan with serine at this position removes the indole ring entirely and replaces it with a small polar hydroxyl. The volume loss is approximately 130 ų — among the largest single-substitution volume losses possible in protein chemistry. The π-stacking interaction with PHE825 is eliminated, the hydrophobic contact to MET781 is broken, and the resulting cavity is too large to be filled by side-chain repacking. The introduced hydroxyl group is polar and small, and would prefer to point toward solvent rather than into the hydrophobic pocket — further destabilizing the local fold.
DynaMut2 returns |ΔΔG| = 2.49 kcal/mol, placing W700S in Category 2 — moderately destabilizing but not gross-misfolding. The fold survives but is energetically compromised in proportion to the lost hydrophobic packing. Note that the W700C variant at the same position (Atlas card adjacent) shows |ΔΔG| of only -0.10 kcal/mol — replacing the indole with a thiol preserves more volume than replacing it with a hydroxyl, even though both are small polar groups. This W → C vs W → S contrast is a clean local example of how packing density, not just chemical class, drives WFS1 destabilization.
Druggability Assessment
This is a pharmacological chaperone candidate. The lost stability comes from a volume mismatch in a packed hydrophobic pocket — not from a broken specific bond or a disrupted catalytic site. The right intervention is a small molecule that stabilizes the wolframin fold globally, shifting the folding equilibrium toward functional protein. The CFTR-corrector analogy applies: rescue the folding yield, not the function.
Worth noting alongside the W700C card: W700 itself sits in a position where multiple pathogenic substitutions are documented, with substitution chemistry directly controlling severity. This makes W700 a useful didactic example of why structural context matters more than the position label alone — the variant cards must always be read at the specific substitution level.
Why this matters
Feed this card to Wolfram Intelligence
Download the W700S 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.