A133T
Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorialAlanine → Threonine at position 133 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram-like + Cataract 41. AlphaMissense 0.878, ΔΔG -1.83 (close to Cat 2 boundary).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | T104 | Gained |
| Hydrogen bond | W129 | W129 | Preserved |
| Hydrogen bond | — | L130 | Gained |
| Hydrogen bond | Q136 | Q136 | Preserved |
| Hydrogen bond | R138 | R138 | Preserved |
| Polar contact | — | P100 | Gained |
| Polar contact | — | Q103 | Gained |
| Polar contact | — | T104 | Gained |
| Polar contact | W129 | W129 | Preserved |
| Polar contact | L130 | L130 | Preserved |
| Polar contact | V131 | V131 | Preserved |
| Polar contact | — | K135 | Gained |
| Polar contact | Q136 | Q136 | Preserved |
| Polar contact | R138 | R138 | Preserved |
| Van der Waals | — | Q103 | Gained |
| Van der Waals | — | V131 | Gained |
| Van der Waals | — | K135 | Gained |
| Van der Waals | Q136 | — | Lost |
| Van der Waals | R138 | R138 | Preserved |
| Hydrophobic | — | P100 | Gained |
| Hydrophobic | Q103 | Q103 | Preserved |
| Hydrophobic | R138 | R138 | Preserved |
| Hydrophobic | A141 | A141 | 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant). 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-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- 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 0.0033% (39 of 1,170,374 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) | 0.0033% | 39 / 1,170,374 | 0 | ~1 in 15000 |
| South Asian · under-sampled | 0.0011% | 1 / 87,486 | 0 | — |
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 133 sits in cytoplasmic domain. Neighbors: LEU132 (2.5 Å), ALA134 (2.5 Å), GLN103 (3.5 Å — long-range), LEU130 (3.8 Å). Adjacent to A126T microregion (A126T at 4.5 Å away in sequence; both in same broader cytoplasmic pocket).
Replacing A133 with threonine introduces polarity into a hydrophobic cytoplasmic pocket. The Q103 long-range contact at 3.5 Å suggests the variant T133 hydroxyl could H-bond with Q103, but the geometric cost is substantial. |ΔΔG| 1.83 close to Cat 2 threshold reflects this.
AlphaMissense 0.878 + Wolfram-like + Cataract 41 confirm severe consequence.
Druggability Assessment
Mechanism: polarity introduction into a hydrophobic cytoplasmic pocket. Therapeutic: same N-terminal microregion as A126T (close in sequence and structure).
Why this matters
Feed this card to Wolfram Intelligence
Download the A133T 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.