T461I
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialThreonine → Isoleucine at position 461 in a connecting loop. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.30 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.30 kcal/mol. Adjacent to E462G (Atlas card).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R457 | R457 | Preserved |
| Hydrogen bond | A458 | A458 | Preserved |
| Hydrogen bond | T464 | T464 | Preserved |
| Hydrogen bond | A465 | A465 | Preserved |
| Hydrogen bond | — | L507 | Gained |
| Polar contact | R457 | R457 | Preserved |
| Polar contact | A458 | A458 | Preserved |
| Polar contact | L459 | L459 | Preserved |
| Polar contact | — | T464 | Gained |
| Polar contact | A465 | A465 | Preserved |
| Van der Waals | A458 | A458 | Preserved |
| Van der Waals | L459 | L459 | Preserved |
| Van der Waals | A465 | A465 | Preserved |
| Van der Waals | Y510 | — | Lost |
| Van der Waals | — | L511 | Gained |
| Hydrophobic | — | L507 | Gained |
| Hydrophobic | Y510 | Y510 | Preserved |
| Hydrophobic | — | L511 | Gained |
| Hydrophobic | — | L514 | 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
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.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity 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
- 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.
Highest in European (non-Finnish): AF 0.00018% (2 of 1,111,798 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00018% | 2 / 1,111,798 | 0 | ~1 in 277950 |
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 461 sits in a connecting loop, immediately upstream of E462 (E462G Atlas card). Neighbors: GLU462 (2.5 Å — the E462G variant position!), ALA460 (2.5 Å), ALA458 (3.6 Å). The E462 contact at 2.5 Å places T461 in direct sequence contact with the E462G pathogenic variant.
The wild-type T461 hydroxyl likely H-bonds with E462's carboxylate, stabilizing the local loop geometry. Replacing T461 with isoleucine eliminates the H-bonding capacity; the E462 carboxylate loses its sequence-neighbor H-bond partner.
|ΔΔG| 0.30 + AM 0.30 below threshold + Wolfram syndrome 1 confirm pathogenicity. The mechanism is loss of T461-E462 H-bond — perturbing the same loop microregion that E462G disrupts.
Druggability Assessment
Mechanism: loss of T461-E462 H-bond. Therapeutic strategy: same E462 loop microregion as E462G.
Why this matters
Feed this card to Wolfram Intelligence
Download the T461I 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.