T455M

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Threonine → Methionine at position 455 · Cytoplasmic loop 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T455 — hydrogen bond to E452

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DynaMut2 mutant · T455M

Mutant M455 — hydrogen bond to A451 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost3 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	A451	A451	Preserved
Hydrogen bond	E452	E452	Preserved
Hydrogen bond	L459	L459	Preserved
Polar contact	—	L447	Gained
Polar contact	A451	A451	Preserved
Polar contact	E452	E452	Preserved
Polar contact	A458	A458	Preserved
Polar contact	L459	L459	Preserved
Van der Waals	E452	E452	Preserved
Hydrophobic	—	Y444	Gained
Hydrophobic	L447	L447	Preserved
Hydrophobic	A451	—	Lost
Hydrophobic	—	E452	Gained
Hydrophobic	M518	—	Lost
Hydrophobic	Y534	Y534	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

1.21kcal/mol

Stabilising — moderate

AlphaMissense

0.467

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome

Population frequency (gnomAD v4)Ultra-rare · AF 0.0051%

cDNA changec.1364C>T

ClinVar accessionVCV001383458

Last evaluated2025/07/11 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — T455M Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Threonine → Methionine at position 455. Cytoplasmic loop 3. ClinVar Uncertain significance, AlphaMissense 0.467, DynaMut2 ΔΔG +1.21 kcal/mol (stabilising).

Identity

Field	Value
Variant	T455M (p.Threonine455Methionine)
DNA change	c.1364C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001383458
Amino acid change	Threonine (T) → Methionine (M)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 455	83.62 — well-folded
Domain	Cytoplasmic loop 3
Position context	Loop region · position 455 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 455 sits in a connecting loop between transmembrane helices. Loop residues are typically solvent-exposed and often contribute to interhelical contacts or serve as recognition sites for binding partners. The wild-type residue is small polar (threonine — hydroxyl); the mutant is hydrophobic sulfur (methionine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4673
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	1.21 (Stabilising)
Job ID	178094722116
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094722116

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/07/11 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	T455M is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1
Cataract 41
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus
Wolfram-like syndrome

Research Path Decision Tree

ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking

Final Schema Categorization

Category 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=1.21 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.21 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.467. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
T455M_molstar_viewer.html — interactive 3D viewer (auto-highlights position 455 with ball-and-stick + neighbors within 5Å)
T455M_variant_card.md — this card (source of truth)
T455M_variant_card.html — styled printable card
T455M_dynamut2_summary.html — clean offline DynaMut2 result card
dynamut2_result.json — structured result data
dynamut2_result_page.html — local snapshot of the Biosig result page (asset URLs absolutized)
T455M_wildtype_interactions.pse / T455M_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the T455M 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 T455M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.