M657T

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Methionine → Threonine at position 657 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type M657 — hydrogen bond to S654

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DynaMut2 mutant · M657T

Mutant T657 — van der waals contact to E655 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S654	S654	Preserved
Hydrogen bond	V659	V659	Preserved
Polar contact	S654	S654	Preserved
Polar contact	E655	E655	Preserved
Polar contact	V659	V659	Preserved
Carbonyl	E655	E655	Preserved
Van der Waals	S654	S654	Preserved
Van der Waals	E655	—	Lost
Van der Waals	—	V659	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

0.45kcal/mol

Stabilising — mild

AlphaMissense

0.629

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00062%

cDNA changec.1970T>C

ClinVar accessionVCV001712009

Last evaluated2025/05/21 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — M657T Variant Card

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

Methionine → Threonine at position 657. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.629, DynaMut2 ΔΔG +0.45 kcal/mol (stabilising).

Identity

Field	Value
Variant	M657T (p.Methionine657Threonine)
DNA change	c.1970T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001712009
Amino acid change	Methionine (M) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 657	51.97 — confident
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 657 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 657 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is hydrophobic sulfur (methionine); the mutant is small polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6288
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.45 (Stabilising)
Job ID	178092129841
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092129841

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/05/21 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	M657T 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|=0.45 < 2 kcal/mol (fold intact) + AlphaMissense 0.629 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|=0.45 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.629. 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
M657T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 657 with ball-and-stick + neighbors within 5Å)
M657T_variant_card.md — this card (source of truth)
M657T_variant_card.html — styled printable card
M657T_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)
M657T_wildtype_interactions.pse / M657T_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 M657T 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 M657T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.