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
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
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 / 1,111,996 | 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 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
Feed this card to Wolfram Intelligence
Download the G674W 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.