A716T
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N714 | N714 | Preserved |
| Hydrogen bond | A719 | A719 | Preserved |
| Hydrogen bond | I720 | I720 | Preserved |
| Polar contact | N714 | N714 | Preserved |
| Polar contact | A719 | A719 | Preserved |
| Polar contact | I720 | I720 | Preserved |
| Van der Waals | N714 | N714 | Preserved |
| Van der Waals | I720 | I720 | Preserved |
| Hydrophobic | I767 | — | Lost |
| Hydrophobic | F770 | F770 | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — A716T Variant Card
Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo
Prepared: May 26, 2026 · Schema target: Category 4 (predicted)
Identity
| Field | Value |
|---|---|
| Variant | A716T |
| DNA change | c.2146G>A |
| Gene | WFS1 |
| Protein | Wolframin (890 aa) |
| UniProt ID | O76024 |
| ClinVar accession | VCV000004520 |
| Amino acid change | A → T at position 716 |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 716 | 83.94 |
| Domain | C-terminal lumenal domain (653-869) |
| UniProt features at this position |
- Chain: 1-890 Wolframin
- Topological domain: 653-869 Lumenal
- Natural variant: 716-716 in DFNA6; dbSNP:rs28937893
Position 716 sits in the C-terminal lumenal domain, in a well-folded region (pLDDT 83.94). Alanine → Threonine is a small chemical change — adding a polar hydroxyl group where a hydrophobic methyl sat.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.2145 |
| am_class | LBen |
| Interpretation | Likely benign — note this disagrees with clinical signal |
DynaMut2
| Field | Value |
|---|---|
| Job ID | 177985952865 |
| ΔΔG (kcal/mol) | -0.8 kcal/mol (Destabilising) |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177985952865 |
Clinical Evidence
| Field | Value |
|---|---|
| ClinVar classification | Pathogenic/Likely pathogenic |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2026/01/24 00:00 |
| Associated conditions | Rare genetic deafness; Monogenic hearing loss; not provided |
Computational vs Clinical Tension
AlphaMissense scores A716T at 0.2145 (Likely Benign) — directly contradicting ClinVar's Pathogenic/Likely pathogenic classification supported by multiple independent submitters. This is the most important computational/clinical tension in the entire pilot set, and explains why the Atlas weights clinical evidence above predictions: AlphaMissense is trained primarily on loss-of-function and structure-destabilizing variants. A dominant-negative variant that disrupts oligomeric assembly without destabilizing the monomer is precisely the kind of mutation it can miss.
Phenotype focus
Autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (DFNA6/14/38)
Carrier story
A716T is the textbook DFNA6 dominant hearing loss variant — a fundamentally different patient population than classical Wolfram. Onset is in childhood, progression is slow, and the phenotype is almost exclusively cochlear.
Mechanism hypothesis
Wolframin likely functions as a multimer in the ER membrane. A dominant variant like A716T poisons the multimer by inserting a malformed subunit, even when the monomer fold itself is fine. The schema's Category 4 (stable fold but functional site disrupted) is the right home for this mechanism.
Files in this folder
AF-O76024-F1-model_v6.pdb— AlphaFold structureA716T_molstar_viewer.html— interactive 3D viewer (auto-loads and highlights position 716)A716T_variant_card.md— this cardA716T_variant_card.html— demo-ready styled version
Final Schema Categorization
Category 4 — Most Druggable (functional disruption with stable fold)
DynaMut2 confirms the fold is intact (only -0.8 kcal/mol). Combined with A716T's documented dominant pattern of inheritance (DFNA6), this points to a dominant-negative mechanism — the monomer folds, but the multimer assembly is poisoned. AlphaMissense missed this because it's trained on monomer-destabilizing variants. The Atlas catches it via clinical evidence.
Every assumption documented. Every score sourced. The Atlas standard.
Feed this card to Wolfram Intelligence
Download the A716T 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.