W639G
Category 4 — Stable Fold, Function DisruptedPathogenicTransmembrane · predictedEditorialTryptophan → Glycine at position 639 inside wolframin's tenth transmembrane helix (TM10). ClinVar Pathogenic. AlphaMissense 0.481 (BELOW the likely-pathogenic threshold), DynaMut2 ΔΔG -1.03 kcal/mol (destabilising). A variant where the structural cost is clear but the AlphaMissense signal is unexpectedly weak.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L635 | L635 | Preserved |
| Hydrogen bond | I636 | I636 | Preserved |
| Hydrogen bond | A642 | A642 | Preserved |
| Hydrogen bond | I643 | I643 | Preserved |
| Polar contact | L635 | L635 | Preserved |
| Polar contact | I636 | I636 | Preserved |
| Polar contact | A642 | A642 | Preserved |
| Polar contact | I643 | I643 | Preserved |
| Carbonyl | — | I636 | Gained |
| Van der Waals | — | L637 | Gained |
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
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 639 sits in the middle of TM10. The AlphaFold model places W639 within 5 Å of VAL638 (2.5 Å), LEU640 (2.5 Å), ILE636 (3.6 Å), LEU635 (3.8 Å), and ALA642 (4.3 Å). The local environment is uniformly hydrophobic — an aliphatic-rich pocket where the wild-type tryptophan's bulky indole ring contributes substantial volume.
Replacing tryptophan with glycine removes the indole ring entirely, leaving a small cavity in the TM10 hydrophobic core. The DynaMut2 |ΔΔG| of 1.03 captures this — the volume mismatch produces meaningful destabilization, larger than most variants in this batch.
Yet AlphaMissense places this at 0.481 — below the 0.564 likely-pathogenic threshold. AM considers this variant likely benign. The discrepancy with ClinVar Pathogenic classification is striking.
Two interpretations: (1) AM's training data may under-represent TM-helix variants in general, leading to systematic under-calling of pathogenicity in this structural context; (2) The variant may be technically pathogenic in specific clinical scenarios (compound heterozygosity, specific tissue contexts) but not in the more general population-genetics sense AM is trained on. The DynaMut2 destabilization (|ΔΔG| 1.03) is real and substantial.
This is a variant where ΔΔG is informative and AM is uncertain.
Druggability Assessment
The mechanism is volume loss in a TM10 hydrophobic packing pocket — the lost tryptophan indole creates a cavity that destabilizes the local membrane-embedded geometry. Therapeutic strategy: site-directed small molecules that fill the cavity left by W639, restoring the wild-type packing volume.
The unexpected AM signal mismatch is itself a finding the Atlas surfaces — variants where structural destabilization is clear but AM training under-calls pathogenicity exist, and they deserve wet-lab characterization to clarify mechanism.
Why this matters
Feed this card to Wolfram Intelligence
Download the W639G 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.