M183V

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

Methionine → Valine at position 183 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type M183 — hydrogen bond to L187

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DynaMut2 mutant · M183V

Mutant V183 — hydrogen bond to F247 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost4 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	A179	A179	Preserved
Hydrogen bond	A180	—	Lost
Hydrogen bond	K186	K186	Preserved
Hydrogen bond	L187	L187	Preserved
Hydrogen bond	F247	—	Lost
Polar contact	A179	A179	Preserved
Polar contact	A180	A180	Preserved
Polar contact	L181	L181	Preserved
Polar contact	W185	—	Lost
Polar contact	K186	K186	Preserved
Polar contact	L187	L187	Preserved
Polar contact	L380	—	Lost
Van der Waals	A179	—	Lost
Van der Waals	—	A180	Gained
Van der Waals	L181	L181	Preserved
Van der Waals	—	L187	Gained
Van der Waals	L230	—	Lost
Van der Waals	—	F247	Gained
Hydrophobic	L187	L187	Preserved
Hydrophobic	—	V207	Gained
Hydrophobic	L230	—	Lost
Hydrophobic	F247	F247	Preserved
Hydrophobic	L380	L380	Preserved
Hydrophobic	F384	F384	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

-0.70kcal/mol

Destabilising — mild

AlphaMissense

0.354

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.00025%

cDNA changec.547A>G

ClinVar accessionVCV003590669

Last evaluated2024/06/04 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — M183V Variant Card

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

Methionine → Valine at position 183. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.354, DynaMut2 ΔΔG -0.70 kcal/mol (destabilising).

Identity

Field	Value
Variant	M183V (p.Methionine183Valine)
DNA change	c.547A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590669
Amino acid change	Methionine (M) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 183	85.81 — 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 183 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is hydrophobic sulfur (methionine); the mutant is small hydrophobic (valine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3537
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.7 (Destabilising)
Job ID	178094721833
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094721833

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/06/04 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	M183V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.70 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.70 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.354. 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
M183V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 183 with ball-and-stick + neighbors within 5Å)
M183V_variant_card.md — this card (source of truth)
M183V_variant_card.html — styled printable card
M183V_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)
M183V_wildtype_interactions.pse / M183V_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 M183V 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 M183V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.