G674R
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialGlycine → Arginine at position 674 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.994, DynaMut2 ΔΔG -0.83 kcal/mol (destabilising). The most charge-heavy substitution at position 674 (compare G674E, 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 | — | W666 | Gained |
| Van der Waals | — | G670 | Gained |
| Van der Waals | — | R676 | Gained |
| Van der Waals | — | K800 | Gained |
| Hydrophobic | — | W666 | 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.
Highest in South Asian: AF 0.0035% (3 of 86,258 alleles), 10.2x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| South Asian | 0.0035% | 3 / 86,258 | 0 | ~1 in 14380 |
| European (non-Finnish) | 0.00018% | 2 / 1,111,996 | 0 | ~1 in 278000 |
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 same neighbors as G674E and G674W. Notably, ARG676 is already at this position; introducing another arginine at 674 creates an unusual two-arginine cluster in a tight loop.
Replacing glycine with arginine here has the same backbone-flexibility loss as G674E (no glycine, no left-handed helix conformation), but the chemistry of the new side chain is opposite. Where G674E introduces negative charge, G674R introduces positive charge. The local environment with ARG676 already in place plus a new R674 produces a positively-charged loop region where the wild-type had a flexible, neutral one.
The |ΔΔG| of 0.83 kcal/mol is larger than G674E's 0.34, reflecting the additional cost of accommodating two adjacent positive charges. The fold still survives — both arginines can extend toward solvent in the lumenal environment — but the local geometry is materially perturbed.
AlphaMissense's 0.994 score is comparable to G674E's, confirming that the mechanism is dominated by loss of glycine flexibility rather than by the specific charge of the introduced residue.
Druggability Assessment
Same mechanism as G674E (loss of glycine flexibility), with charge sign opposite. Therapeutic strategy: same as G674E — stabilize the wild-type C673-G674-P675 backbone geometry. A drug designed for one of these three variants at position 674 likely rescues all three.
The two-arginine cluster (R674 + R676 in the variant) is a structurally unusual feature that might also offer a specific small-molecule docking handle — a compound that engages both positive charges simultaneously could selectively bind the variant.
Why this matters
Feed this card to Wolfram Intelligence
Download the G674R 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.