V536L

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Valine → Leucine at position 536 · Transmembrane helix 8 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type V536 — hydrogen bond to P533

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DynaMut2 mutant · V536L

Mutant L536 — hydrogen bond to V532 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost2 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V532	V532	Preserved
Hydrogen bond	P533	P533	Preserved
Hydrogen bond	W540	W540	Preserved
Polar contact	V532	V532	Preserved
Polar contact	P533	P533	Preserved
Polar contact	Y534	Y534	Preserved
Polar contact	M539	—	Lost
Polar contact	W540	W540	Preserved
Van der Waals	—	F408	Gained
Hydrophobic	T361	T361	Preserved
Hydrophobic	—	V364	Gained
Hydrophobic	Y405	—	Lost
Hydrophobic	F408	F408	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

-0.40kcal/mol

Destabilising — mild

AlphaMissense

0.659

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 0.00099%

cDNA changec.1606G>C

ClinVar accessionVCV002151042

Last evaluated2024/09/06 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — V536L Variant Card

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

Valine → Leucine at position 536. Transmembrane helix 8. ClinVar Uncertain significance, AlphaMissense 0.659, DynaMut2 ΔΔG -0.40 kcal/mol (destabilising).

Identity

Field	Value
Variant	V536L (p.Valine536Leucine)
DNA change	c.1606G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002151042
Amino acid change	Valine (V) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 536	90.62 — well-folded
Domain	Transmembrane helix 8
Position context	Inside Transmembrane helix 8 · position 536 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 536 sits in a transmembrane helix (Transmembrane helix 8). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is small hydrophobic (valine — branched); the mutant is medium hydrophobic (leucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6594
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.4 (Destabilising)
Job ID	178092128557
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092128557

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/09/06 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	V536L 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|=0.40 < 2 kcal/mol (fold intact) + AlphaMissense 0.659 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|=0.40 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.659. 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
V536L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 536 with ball-and-stick + neighbors within 5Å)
V536L_variant_card.md — this card (source of truth)
V536L_variant_card.html — styled printable card
V536L_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)
V536L_wildtype_interactions.pse / V536L_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 V536L 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 V536L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.