G674V
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialGlycine → Valine at position 674 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic, monogenic hearing loss. AlphaMissense 0.983, DynaMut2 ΔΔG -0.24 kcal/mol (destabilising). The FOURTH pathogenic substitution catalogued at position 674 in the Atlas — with G674E, G674R, G674W.
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 |
| Polar contact | G670 | G670 | Preserved |
| Polar contact | R676 | R676 | Preserved |
| Polar contact | A677 | A677 | Preserved |
| Polar contact | W678 | W678 | Preserved |
| Van der Waals | — | G670 | Gained |
| Van der Waals | — | R676 | Gained |
| Hydrophobic | — | W666 | Gained |
| Hydrophobic | — | W678 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 674 sits in wolframin's C-terminal lumenal domain. Same neighbor environment as the G674E/R/W series: CYS673 (2.5 Å), PRO675 (2.5 Å), GLY670 (3.1 Å), TRP678 (4.0 Å), ARG676 (4.5 Å).
Replacing glycine with valine removes the wild-type backbone flexibility but introduces a more conservative side chain than G674E/R/W. The branched aliphatic valine fits the local environment better than charged or bulky alternatives — the |ΔΔG| of 0.24 is the smallest of the G674 series.
Yet AlphaMissense's 0.983 plus monogenic hearing loss clinical evidence confirm severe functional consequence. The mechanism is still loss of glycine's structural flexibility role, even though the variant residue's chemistry is conservative.
G674V is the most chemically conservative substitution at position 674 — and the smallest |ΔΔG| in the series — yet still pathogenic. This confirms the Atlas's hypothesis that the wild-type glycine at this position is structurally irreplaceable regardless of which residue substitutes.
Druggability Assessment
The mechanism is loss of glycine flexibility at position 674. Therapeutic strategy: same target as G674E/R/W — restore the wild-type backbone geometry at the C673-G674-P675 microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the G674V 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.