N714T
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialAsparagine → Threonine at position 714 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic, associated with rare genetic deafness. AlphaMissense 0.927, DynaMut2 ΔΔG -0.23 kcal/mol (destabilising). A conservative polar-to-polar substitution with subtle but consequential mechanism.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A716 | — | Lost |
| Hydrogen bond | E717 | — | Lost |
| Hydrogen bond | S718 | S718 | Preserved |
| Hydrogen bond | I767 | — | Lost |
| Hydrogen bond | D771 | D771 | Preserved |
| Polar contact | A716 | — | Lost |
| Polar contact | E717 | — | Lost |
| Polar contact | S718 | S718 | Preserved |
| Polar contact | I767 | — | Lost |
| Polar contact | D771 | D771 | Preserved |
| Van der Waals | A716 | — | Lost |
| Van der Waals | E717 | — | Lost |
| Van der Waals | — | S718 | Gained |
| Hydrophobic | E717 | E717 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Pathogenic for Hearing loss, inheritance unstated (inheritance not specified).
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Rare genetic deafness
- 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 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places N714 within 5 Å of SER715 (2.4 Å), ASP713 (2.5 Å — likely H-bond partner), PHE770 (4.4 Å, long-range), ALA716 (4.4 Å), and ASP771 (4.7 Å, long-range). The local environment is unusual — two adjacent aspartates in spatial proximity (D713 immediately upstream, D771 across the fold), suggesting N714 sits in a polar interaction network.
The wild-type asparagine's amide carries both H-bond donor (NH2) and acceptor (C=O) capacity. The wild-type N714 likely engages D713 and possibly D771 across the fold through this dual H-bond chemistry.
Replacing asparagine with threonine swaps the amide for a hydroxyl. Threonine's hydroxyl has H-bond donor AND acceptor capacity through the same oxygen, but the geometry differs from asparagine's amide. The H-bond network to D713/D771 reorganizes; some contacts may be preserved, others lost.
The |ΔΔG| of 0.23 is small — the fold barely registers the swap. But AlphaMissense's 0.927 score and the clinical evidence (rare genetic deafness) confirm functional consequence. The mechanism is likely subtle reorganization of the local H-bond network that perturbs partner-protein recognition geometry.
Druggability Assessment
The mechanism is reorganization of the H-bond network involving D713 (immediate neighbor) and D771 (longer-range). Therapeutic strategy: site-directed small molecules at the D713-N714-D771 network. The pathogenic mechanism is fine-grained H-bond geometry rather than gross structural disruption.
Why this matters
Feed this card to Wolfram Intelligence
Download the N714T 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.