G736R
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialGlycine → Arginine at position 736 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.984, DynaMut2 ΔΔG -0.92 kcal/mol (destabilising). Another glycine-removal variant — paralleling the G674 cluster mechanism.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | — | E717 | Gained |
| Hydrogen bond | — | E717 | Gained |
| Hydrogen bond | R732 | R732 | Preserved |
| Polar contact | — | E717 | Gained |
| Polar contact | R732 | R732 | Preserved |
| Polar contact | — | C765 | Gained |
| Polar contact | H766 | H766 | Preserved |
| Carbonyl | — | R732 | Gained |
| Carbonyl | — | C733 | Gained |
| Carbonyl | H766 | H766 | Preserved |
| Van der Waals | — | R732 | Gained |
| Van der Waals | H766 | H766 | Preserved |
| Hydrophobic | — | R732 | Gained |
| Hydrophobic | — | I767 | 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. |
|---|---|---|---|---|
| South Asian · under-sampled | 0.021% | 1 / 4,832 | 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 736 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places G736 within 5 Å of GLU737 (2.4 Å), TYR735 (2.5 Å), ARG732 (3.1 Å — a four-residue-back contact), HIS766 (3.3 Å — long-range), and ILE767 (4.1 Å). The local environment combines polar (E737, Y735), basic (R732), and titratable (H766) residues with a hydrophobic contact (I767).
The wild-type glycine at 736 plays the same backbone-flexibility role described for the G674 cluster. The neighbor analysis shows particularly tight packing — multiple residues within 4 Å — suggesting the local fold is geometrically constrained, and glycine's lack of side chain is what enables that geometry. Notably, ARG732 sits 3.1 Å away; the wild-type G736 plus R732 form a tight cluster where a single basic residue dominates the local electrostatic character.
Replacing glycine with arginine adds a second positive charge at 3.1 Å from the existing R732. This produces a two-arginine cluster similar to the G674R case — local electrostatic repulsion between adjacent positive charges plus the loss of glycine's backbone flexibility.
The |ΔΔG| of 0.92 reflects this combined cost. AlphaMissense's 0.984 score captures the severe functional consequence — likely disruption of a specific lumenal interaction surface where R732 alone served as the recognized positive charge.
Druggability Assessment
The mechanism is loss of glycine flexibility plus introduction of a second positive charge adjacent to R732 — disrupting a likely partner-recognition surface where R732 alone was the wild-type signature.
Therapeutic strategy: site-directed small molecules at the R732-G736-Y735 microregion. Pharmacological chaperones biasing the local backbone toward the wild-type glycine-enabled geometry.
Why this matters
Feed this card to Wolfram Intelligence
Download the G736R 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.