T156M

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Threonine → Methionine at position 156 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T156 — hydrogen bond to N159

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DynaMut2 mutant · T156M

Mutant M156 — hydrogen bond contact to N159 lost

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Bond changes · DynaMut2 interaction analysis

1 lost3 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	N159	N159	Preserved
Hydrogen bond	E160	E160	Preserved
Polar contact	E158	E158	Preserved
Polar contact	N159	N159	Preserved
Polar contact	E160	E160	Preserved
Van der Waals	E158	—	Lost
Van der Waals	N159	N159	Preserved
Van der Waals	—	E160	Gained
Hydrophobic	—	E158	Gained
Hydrophobic	—	N159	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

DynaMut2 ΔΔG

0.25kcal/mol

Stabilising — mild

AlphaMissense

0.626

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00043%

cDNA changec.467C>T

ClinVar accessionVCV002734642

Last evaluated2023/08/07 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — T156M Variant Card

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

Threonine → Methionine at position 156. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.626, DynaMut2 ΔΔG +0.25 kcal/mol (stabilising).

Identity

Field	Value
Variant	T156M (p.Threonine156Methionine)
DNA change	c.467C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002734642
Amino acid change	Threonine (T) → Methionine (M)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 156	89.25 — well-folded
Domain	N-terminal cytoplasmic (intrinsically disordered)
Position context	N-terminal cytoplasmic (intrinsically disordered)
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 156 sits in N-terminal cytoplasmic (intrinsically disordered). 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	0.6264
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.25 (Stabilising)
Job ID	178092130017
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092130017

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/08/07 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	T156M is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.25 < 2 kcal/mol (fold intact) + AlphaMissense 0.626 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.25 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.626. 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
T156M_molstar_viewer.html — interactive 3D viewer (auto-highlights position 156 with ball-and-stick + neighbors within 5Å)
T156M_variant_card.md — this card (source of truth)
T156M_variant_card.html — styled printable card
T156M_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)
T156M_wildtype_interactions.pse / T156M_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 T156M 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 T156M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.