A133T

Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorial

Alanine → Threonine at position 133 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Alanine → 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

Wild-type reference

Wild-type A133 — hydrogen bond to R138

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DynaMut2 mutant · A133T

Mutant T133 — van der waals contact to R138 lost

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Bond changes · DynaMut2 interaction analysis

1 lost10 gained12 preserved

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

DynaMut2 ΔΔG

-1.83kcal/mol

Destabilising — moderate

AlphaMissense

0.878

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsWolfram-like syndrome; Cataract 41

InheritanceWolfram-like + Cataract 41 documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0025%

cDNA changec.397G>A

ClinVar accessionVCV001331467

Last evaluated2025/11/05 00:00

Observed at very low frequency in gnomAD.

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.

Amino-acid chemistry

Alanine (A) → Threonine (T) — small methyl-bearing hydrophobic replaced by small polar hydroxyl.

Position in the protein

N-terminal cytoplasmic domain · position 133 (pLDDT 92).

Druggability Assessment

Category 3/4 — Most Druggable (near Cat 2 boundary). |ΔΔG| = 1.83 — closest to Cat 2 threshold in this batch. AlphaMissense 0.878 confirms severe consequence.

Mechanism: polarity introduction into a hydrophobic cytoplasmic pocket. Therapeutic: same N-terminal microregion as A126T (close in sequence and structure).

Why this matters

A133T + A126T together establish the 126-133 cytoplasmic microregion as a multi-variant target.

Therapeutic Strategy Handoff · prediction

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.

Download A133T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A

Natural variant133–133 · in WFS1; dbSNP:rs372249044