G674W
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialGlycine → Tryptophan at position 674 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.991, DynaMut2 ΔΔG -0.77 kcal/mol (destabilising). The largest substitution at position 674 — backbone flexibility loss combined with massive volume increase.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | G670 | G670 | Preserved |
| Hydrogen bond | A677 | A677 | Preserved |
| Hydrogen bond | W678 | W678 | Preserved |
| Hydrogen bond | — | K800 | Gained |
| Polar contact | G670 | G670 | Preserved |
| Polar contact | R676 | R676 | Preserved |
| Polar contact | A677 | A677 | Preserved |
| Polar contact | W678 | W678 | Preserved |
| Aromatic / π | — | W666 | Gained |
| Aromatic / π | — | F783 | Gained |
| Van der Waals | — | W666 | Gained |
| Van der Waals | — | G670 | Gained |
| Van der Waals | — | R676 | Gained |
| Van der Waals | — | A677 | Gained |
| Hydrophobic | — | W666 | Gained |
| Hydrophobic | — | F783 | Gained |
| Hydrophobic | — | K800 | 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 674 sits in wolframin's C-terminal lumenal domain, between CYS673 (2.5 Å), PRO675 (2.5 Å), GLY670 (3.1 Å), TRP678 (4.0 Å), and ARG676 (4.5 Å). The TRP678 contact at 4.0 Å is structurally significant: an existing tryptophan four residues downstream in the chain.
Replacing glycine with tryptophan at position 674 has two simultaneous costs. First, the glycine backbone flexibility is gone — the local conformation must rearrange to accommodate any non-glycine residue. Second, the introduced indole ring is roughly an order of magnitude larger than glycine's missing side chain. The local pocket simply does not have space for a tryptophan in the wild-type geometry; substantial local rearrangement is forced.
The combination produces a |ΔΔG| of 0.77 kcal/mol — comparable to G674R's 0.83, both larger than G674E's 0.34. The fold absorbs the substitution, but at meaningful cost. The new W674 plus the existing W678 creates a two-tryptophan cluster in the loop, which might engage in π-stacking with each other in the variant's rearranged geometry — but this is an artifact of the mutation, not a functional feature.
AlphaMissense's 0.991 score confirms severe functional consequence. The pathogenicity mechanism is the same as G674E/G674R: removal of glycine flexibility at a position that requires it, plus secondary disruption from the specific introduced residue's properties.
Druggability Assessment
The mechanism combines glycine flexibility loss (shared across the G674E/R/W series) with volume mismatch (specific to G674W). Therapeutic strategy: same backbone-geometry stabilization as G674E and G674R. A drug aimed at the position 674 microregion targets all three known substitutions.
The G674W variant's introduced aromatic ring could be exploited by a drug designed to displace the variant tryptophan back into a wild-type-like geometry — a selective rescue strategy that wouldn't work for G674E or G674R.
Why this matters
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