V195M

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

Valine → Methionine at position 195 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type V195 — hydrogen bond to I242

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DynaMut2 mutant · V195M

Mutant M195 — hydrogen bond to Y184 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost3 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y184	—	Lost
Hydrogen bond	—	E199	Gained
Hydrogen bond	Y241	Y241	Preserved
Hydrogen bond	I242	I242	Preserved
Polar contact	—	N188	Gained
Polar contact	Y241	—	Lost
Polar contact	I242	I242	Preserved
Van der Waals	N188	—	Lost
Van der Waals	—	E199	Gained
Van der Waals	I242	I242	Preserved
Hydrophobic	N188	N188	Preserved
Hydrophobic	K192	—	Lost
Hydrophobic	E199	E199	Preserved
Hydrophobic	L200	L200	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

-0.22kcal/mol

Destabilising — mild

AlphaMissense

0.356

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 conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.583G>A

ClinVar accessionVCV003621440

Last evaluated2024/02/20 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — V195M Variant Card

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

Valine → Methionine at position 195. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.356, DynaMut2 ΔΔG -0.22 kcal/mol (destabilising).

Identity

Field	Value
Variant	V195M (p.Valine195Methionine)
DNA change	c.583G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003621440
Amino acid change	Valine (V) → Methionine (M)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 195	83.19 — 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 195 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is small hydrophobic (valine — branched); 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	0.3556
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.22 (Destabilising)
Job ID	178094706898
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094706898

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/02/20 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	V195M 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.22 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.22 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.356. 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
V195M_molstar_viewer.html — interactive 3D viewer (auto-highlights position 195 with ball-and-stick + neighbors within 5Å)
V195M_variant_card.md — this card (source of truth)
V195M_variant_card.html — styled printable card
V195M_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)
V195M_wildtype_interactions.pse / V195M_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 V195M 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 V195M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.