T337I
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialThreonine → Isoleucine at position 337 in a connecting loop. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.865, DynaMut2 ΔΔG -0.48 kcal/mol (destabilising). pLDDT 65 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N335 | N335 | Preserved |
| Hydrogen bond | F340 | F340 | Preserved |
| Hydrogen bond | F341 | F341 | Preserved |
| Polar contact | N335 | N335 | Preserved |
| Polar contact | D339 | D339 | Preserved |
| Polar contact | F340 | F340 | Preserved |
| Polar contact | F341 | F341 | Preserved |
| Van der Waals | — | N335 | Gained |
| Van der Waals | F340 | — | Lost |
| Van der Waals | F341 | — | Lost |
| Hydrophobic | — | D339 | Gained |
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
- transmembrane position; predictor benchmarked on soluble proteins
- pLDDT 65.12 below 70
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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: 2★ multiple submitters, no conflicts. 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 337 sits in a connecting loop near TM2. The AlphaFold model places T337 within 5 Å of ILE338 (2.4 Å), LEU336 (2.5 Å), ASN335 (4.1 Å), ASP339 (4.2 Å), and PHE340 (4.4 Å). The local environment is mixed polar-hydrophobic.
The wild-type threonine's hydroxyl likely H-bonds with the nearby N335 or D339. Replacing it with isoleucine eliminates the H-bonding capacity. The fold absorbs the substitution (|ΔΔG| 0.48), but the local H-bond network reorganizes.
AlphaMissense 0.865 + Wolfram 1 confirm pathogenic consequence. The mechanism is loss of T337's H-bonding role in the loop's polar network. pLDDT 65 is borderline; structural details deserve wet-lab confirmation.
Druggability Assessment
Mechanism is loss of T337 H-bonding role. Therapeutic strategy: site-directed at the connecting loop polar network.
Why this matters
Feed this card to Wolfram Intelligence
Download the T337I 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.