L531F

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Leucine → Phenylalanine at position 531 · Cytoplasmic loop 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L531 — hydrogen bond to G526

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DynaMut2 mutant · L531F

Mutant F531 — hydrogen bond to Y534 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost3 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	G526	G526	Preserved
Hydrogen bond	T527	T527	Preserved
Hydrogen bond	Y534	Y534	Preserved
Hydrogen bond	L535	L535	Preserved
Polar contact	G526	G526	Preserved
Polar contact	T527	T527	Preserved
Polar contact	Y534	Y534	Preserved
Polar contact	L535	L535	Preserved
Aromatic / π	—	F515	Gained
Carbonyl	Y534	—	Lost
Van der Waals	—	F515	Gained
Van der Waals	T527	—	Lost
Van der Waals	—	L535	Gained
Hydrophobic	F515	F515	Preserved
Hydrophobic	A519	—	Lost
Hydrophobic	L535	L535	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

-0.73kcal/mol

Destabilising — mild

AlphaMissense

0.602

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 0.00068%

cDNA changec.1591C>T

ClinVar accessionVCV001991057

Last evaluated2023/11/25 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — L531F Variant Card

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

Leucine → Phenylalanine at position 531. Cytoplasmic loop 4. ClinVar Uncertain significance, AlphaMissense 0.602, DynaMut2 ΔΔG -0.73 kcal/mol (destabilising).

Identity

Field	Value
Variant	L531F (p.Leucine531Phenylalanine)
DNA change	c.1591C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001991057
Amino acid change	Leucine (L) → Phenylalanine (F)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 531	84.62 — well-folded
Domain	Cytoplasmic loop 4
Position context	Loop region · position 531 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 531 sits in a connecting loop between transmembrane helices. Loop residues are typically solvent-exposed and often contribute to interhelical contacts or serve as recognition sites for binding partners. The wild-type residue is medium hydrophobic (leucine — branched); the mutant is large aromatic hydrophobic (phenylalanine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6022
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.73 (Destabilising)
Job ID	178092131747
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092131747

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/11/25 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	L531F 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|=0.73 < 2 kcal/mol (fold intact) + AlphaMissense 0.602 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|=0.73 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.602. 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
L531F_molstar_viewer.html — interactive 3D viewer (auto-highlights position 531 with ball-and-stick + neighbors within 5Å)
L531F_variant_card.md — this card (source of truth)
L531F_variant_card.html — styled printable card
L531F_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)
L531F_wildtype_interactions.pse / L531F_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 L531F 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 L531F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.