M229T

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Methionine → Threonine at position 229 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type M229 — hydrogen bond to K225

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DynaMut2 mutant · M229T

Mutant T229 — hydrogen bond to N373 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost0 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K225	K225	Preserved
Hydrogen bond	Q226	Q226	Preserved
Hydrogen bond	R232	R232	Preserved
Hydrogen bond	L233	L233	Preserved
Hydrogen bond	N373	N373	Preserved
Hydrogen bond	T376	T376	Preserved
Hydrogen bond	L377	—	Lost
Polar contact	K225	K225	Preserved
Polar contact	Q226	Q226	Preserved
Polar contact	R227	R227	Preserved
Polar contact	R232	R232	Preserved
Polar contact	L233	L233	Preserved
Polar contact	T376	T376	Preserved
Van der Waals	R227	R227	Preserved
Hydrophobic	N373	—	Lost
Hydrophobic	L377	—	Lost

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

-1.11kcal/mol

Destabilising — moderate

AlphaMissense

0.587

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.0022%

cDNA changec.686T>C

ClinVar accessionVCV001439615

Last evaluated2024/03/11 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — M229T Variant Card

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

Methionine → Threonine at position 229. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.587, DynaMut2 ΔΔG -1.11 kcal/mol (destabilising).

Identity

Field	Value
Variant	M229T (p.Methionine229Threonine)
DNA change	c.686T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001439615
Amino acid change	Methionine (M) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 229	79.19 — 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 229 sits in N-terminal cytoplasmic (intrinsically disordered). 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	0.5869
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.11 (Destabilising)
Job ID	178092133744
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092133744

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/03/11 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	M229T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=1.11 < 2 kcal/mol (fold intact) + AlphaMissense 0.587 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|=1.11 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.587. 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
M229T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 229 with ball-and-stick + neighbors within 5Å)
M229T_variant_card.md — this card (source of truth)
M229T_variant_card.html — styled printable card
M229T_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)
M229T_wildtype_interactions.pse / M229T_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 M229T 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 M229T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.