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
- 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 at very low frequency in gnomAD.
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.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
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) · under-sampled | 0.000090% | 1 / 1,112,010 | 0 | — |
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 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.