A684G
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAlanine → Glycine at position 684 in lumenal domain. ClinVar Conflicting including type 2 diabetes. AlphaMissense 0.808, ΔΔG -0.38. THIRD substitution at position 684 (with A684T, A684V).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Q687 | Q687 | Preserved |
| Hydrogen bond | I688 | I688 | Preserved |
| Polar contact | N682 | N682 | Preserved |
| Polar contact | Q687 | Q687 | Preserved |
| Polar contact | I688 | I688 | Preserved |
| Van der Waals | N682 | N682 | Preserved |
| Van der Waals | I688 | I688 | Preserved |
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 Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant). 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.
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0019% (23 of 1,179,952 alleles), in line with the global figure.
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) | 0.0019% | 23 / 1,179,952 | 0 | ~1 in 25650 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,464 | 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 684 same neighbors as A684T/V: MET683 (2.5 Å), ARG685 (2.5 Å — R685P), GLN687 (4.0 Å — Q687H), ASN682 (4.0 Å), THR686 (4.4 Å).
A684G is the third substitution at position 684 — eliminating side chain entirely, introducing glycine backbone flexibility. The variant fold may shift more substantially than A684T's hydroxyl-introduction or A684V's volume-increase because of the backbone freedom.
ΔΔG 0.38 + AM 0.808 + T2D confirm severe consequence.
Druggability Assessment
Mechanism: backbone-flexibility introduction in the R685 microregion. Therapeutic: same A684 cluster.
Why this matters
Feed this card to Wolfram Intelligence
Download the A684G 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.