R708L
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialArginine → Leucine at position 708 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic, auditory neuropathy. AlphaMissense 0.954, DynaMut2 ΔΔG +0.20 kcal/mol — STABILISING. A charge-loss variant where the fold tightens slightly.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E776 | — | Lost |
| Hydrogen bond | F775 | F775 | Preserved |
| Hydrogen bond | E776 | E776 | Preserved |
| Polar contact | — | T710 | Gained |
| Polar contact | F775 | — | Lost |
| Polar contact | E776 | E776 | Preserved |
| Carbonyl | F775 | — | Lost |
| Van der Waals | F775 | — | Lost |
| Van der Waals | E776 | E776 | Preserved |
| Hydrophobic | — | Y706 | Gained |
| Hydrophobic | T710 | — | Lost |
| Hydrophobic | E776 | E776 | 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 Likely pathogenic for Hearing loss, inheritance unstated (inheritance not specified).
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Auditory neuropathy
- This rests on a single submitter (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★ 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. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,892 | 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 708 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places R708 within 5 Å of VAL709 (2.4 Å), VAL707 (2.5 Å — same V707 as V707F Atlas card), and GLU776 (3.8 Å — likely salt-bridge partner).
The wild-type arginine likely forms an intramolecular salt bridge with E776 across the lumenal fold. Replacing R708 with leucine eliminates that salt bridge entirely. The DynaMut2 ΔΔG of +0.20 (stabilising) reflects that the leucine packs more efficiently into the hydrophobic V707-V709 local environment than the long arginine side chain did.
AlphaMissense's 0.954 + auditory neuropathy clinical evidence confirm severe functional consequence. The mechanism is loss of the R708-E776 salt bridge that the wild-type fold relied on, even though the local packing improves.
Druggability Assessment
Mechanism is loss of R708-E776 salt bridge. Therapeutic strategy: bridge restoration through site-directed small molecules at the E776 microregion. Combined with V707F (adjacent position), drug discovery has convergent targets.
Why this matters
Feed this card to Wolfram Intelligence
Download the R708L 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.