G674E
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialGlycine → Glutamate at position 674 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic, associated with DFNA6 hearing loss. AlphaMissense 0.996 (near-maximum), DynaMut2 ΔΔG -0.34 kcal/mol (destabilising). One of three pathogenic substitutions catalogued at position 674 in the Atlas (with G674R and 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 |
| Van der Waals | — | A677 | Gained |
| Hydrophobic | — | W666 | Gained |
| Hydrophobic | — | Y669 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Pathogenic for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- 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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
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. The AlphaFold model places G674 within 5 Å of CYS673 (2.5 Å), PRO675 (2.5 Å), GLY670 (3.1 Å), TRP678 (4.0 Å), and ARG676 (4.5 Å). The local environment is dense — a cysteine and a proline immediately flank G674, suggesting a structurally constrained turn or loop region.
The wild-type glycine at 674 plays a backbone-flexibility role. Glycine's lack of a side chain permits backbone conformations that other amino acids cannot adopt — particularly in tight turns and bends. The proximity to CYS673 (which may participate in disulfide chemistry, see C690R/C690Y atlas cards for the C673 contact discussion) and to PRO675 (a backbone-constraining residue) suggests G674 sits at a deliberately flexible position in a deliberately rigid region.
Replacing glycine with glutamate disrupts this on two axes: the backbone flexibility the wild-type provided is gone (glutamate's side chain constrains phi/psi angles), and a negatively-charged carboxylate is introduced into a tight local environment. The ΔΔG of 0.34 indicates the fold absorbs this. AlphaMissense's 0.996 score reflects the severity of the functional consequence.
Compare with G674R and G674W at the same position (Atlas cards adjacent): all three substitutions are pathogenic, with different mechanisms (charge introduction for G674E and G674R; volume increase for G674W) but the same root cause — removal of glycine's backbone flexibility from a position that requires it.
Druggability Assessment
The mechanism is loss of backbone flexibility plus charge introduction into a constrained loop region. Therapeutic strategy: a small molecule that stabilizes the wild-type backbone geometry around the C673-G674-P675 region, or a chaperone biasing the local fold against the variant's preferred geometry.
Compare with G674R (different charge sign) and G674W (volume increase) at the same position — three Atlas variants converge on a single therapeutic target geometry.
Why this matters
Feed this card to Wolfram Intelligence
Download the G674E 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.