N714S
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialAsparagine → Serine at position 714 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for DFNA6 hearing loss. AlphaMissense 0.640 (just above threshold), DynaMut2 ΔΔG -0.49 kcal/mol (destabilising). Third Atlas variant at position 714 (with N714T, N714K).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A716 | — | Lost |
| Hydrogen bond | E717 | E717 | Preserved |
| Hydrogen bond | S718 | S718 | Preserved |
| Hydrogen bond | I767 | — | Lost |
| Hydrogen bond | D771 | D771 | Preserved |
| Polar contact | A716 | — | Lost |
| Polar contact | E717 | E717 | Preserved |
| Polar contact | S718 | S718 | Preserved |
| Polar contact | I767 | — | Lost |
| Polar contact | D771 | — | Lost |
| Van der Waals | A716 | — | Lost |
| Van der Waals | E717 | E717 | Preserved |
| Van der Waals | — | S718 | Gained |
| Hydrophobic | E717 | — | Lost |
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 Likely 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
- 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.
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 714 same neighbor environment as N714T and N714K: SER715 (2.4 Å), ASP713 (2.5 Å), PHE770 (4.4 Å), ALA716 (4.4 Å), ASP771 (4.7 Å — partner of D771H Atlas card).
N714S is the most conservative substitution in the N714 series — replacing asparagine with serine preserves H-bonding capacity but changes the geometry from amide to hydroxyl. The D713-N714-D771 polar network reorganizes; the new S714 hydroxyl is shorter than asparagine's amide arm.
The |ΔΔG| of 0.49 reflects fold accommodation. AlphaMissense's 0.640 is the lowest in the N714 series — borderline above the 0.564 threshold — yet ClinVar Likely Pathogenic with DFNA6 establishes clinical pathogenicity. The mechanism is fine-grained H-bond network adjustment.
Druggability Assessment
Mechanism is fine-grained H-bond network reorganization at the D713-N714-D771 polar cluster. Therapeutic strategy: same microregion as N714T, N714K, D771H.
Why this matters
Feed this card to Wolfram Intelligence
Download the N714S 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.