I802T
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialIsoleucine → Threonine at position 802 in lumenal domain. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.851, ΔΔG -1.99 — RIGHT AT Cat 2 boundary.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | T778 | T778 | Preserved |
| Hydrogen bond | V779 | V779 | Preserved |
| Hydrogen bond | M781 | — | Lost |
| Polar contact | T778 | — | Lost |
| Polar contact | V779 | V779 | Preserved |
| Van der Waals | M781 | — | Lost |
| Van der Waals | F840 | F840 | Preserved |
| Hydrophobic | W666 | — | Lost |
| Hydrophobic | W700 | — | Lost |
| Hydrophobic | M781 | — | Lost |
| Hydrophobic | L804 | L804 | Preserved |
| Hydrophobic | F825 | — | Lost |
| Hydrophobic | P838 | P838 | Preserved |
| Hydrophobic | F840 | F840 | 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 Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Submitters conflict on this classification (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★ conflicting classifications. 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 802 sits in the lumenal domain. Neighbors: VAL803 (2.4 Å), ASP801 (2.5 Å — partner of D801G), VAL779 (3.9 Å — V779G outlier region!), PRO838 (4.1 Å).
Replacing I802 with threonine introduces polarity into a hydrophobic environment near both D801G's salt-bridge region and V779G's Cat 2 outlier site. The |ΔΔG| of 1.99 is the largest in this batch — RIGHT AT the Category 2 threshold. The variant nearly bridges the fold-intact / moderately-destabilizing boundary.
AlphaMissense 0.851 + Wolfram + Wolfram-like confirm severe consequence.
Druggability Assessment
Mechanism: polarity in hydrophobic environment + perturbation of V779 outlier region. Therapeutic: site-directed at the V779-D801-I802 microregion — chaperone screening may also be warranted given near-Cat-2 stability.
Why this matters
Feed this card to Wolfram Intelligence
Download the I802T 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.