L565V

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

Leucine → Valine at position 565 · Lumenal loop 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L565 — hydrogen bond to A569

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DynaMut2 mutant · L565V

Mutant V565 — polar contact to L567 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost3 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I561	I561	Preserved
Hydrogen bond	—	G562	Gained
Hydrogen bond	F568	F568	Preserved
Hydrogen bond	A569	A569	Preserved
Polar contact	I561	I561	Preserved
Polar contact	—	G562	Gained
Polar contact	L567	—	Lost
Polar contact	F568	F568	Preserved
Polar contact	A569	A569	Preserved
Van der Waals	—	I561	Gained
Van der Waals	L567	—	Lost
Van der Waals	A569	A569	Preserved
Hydrophobic	A569	A569	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

0.42kcal/mol

Stabilising — mild

AlphaMissense

0.428

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance/Uncertain risk allele

Review statuscriteria provided, multiple submitters, no conflicts

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.0046%

cDNA changec.1693C>G

ClinVar accessionVCV000229638

Last evaluated2026/01/08 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — L565V Variant Card

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

Leucine → Valine at position 565. Lumenal loop 4. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.428, DynaMut2 ΔΔG +0.42 kcal/mol (stabilising).

Identity

Field	Value
Variant	L565V (p.Leucine565Valine)
DNA change	c.1693C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000229638
Amino acid change	Leucine (L) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 565	79.31 — well-folded
Domain	Lumenal loop 4
Position context	C-terminal lumenal domain · position 565 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 565 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is medium hydrophobic (leucine — branched); 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	0.4277
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.42 (Stabilising)
Job ID	178094708374
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094708374

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/01/08 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	L565V 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-like syndrome
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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.42 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.42 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.428. 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
L565V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 565 with ball-and-stick + neighbors within 5Å)
L565V_variant_card.md — this card (source of truth)
L565V_variant_card.html — styled printable card
L565V_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)
L565V_wildtype_interactions.pse / L565V_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 L565V 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 L565V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.