A569T

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

Alanine → Threonine at position 569 · Lumenal loop 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A569 — hydrogen bond to L565

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DynaMut2 mutant · A569T

Mutant T569 — van der waals contact to L565 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L565	L565	Preserved
Hydrogen bond	I572	I572	Preserved
Hydrogen bond	L573	L573	Preserved
Polar contact	L565	L565	Preserved
Polar contact	I572	I572	Preserved
Polar contact	L573	L573	Preserved
Carbonyl	I572	I572	Preserved
Van der Waals	L565	L565	Preserved
Van der Waals	I572	—	Lost
Hydrophobic	L565	L565	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

-0.81kcal/mol

Destabilising — mild

AlphaMissense

0.429

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

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 0.00031%

cDNA changec.1705G>A

ClinVar accessionVCV000229639

Last evaluated2021/12/22 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A569T Variant Card

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

Alanine → Threonine at position 569. Lumenal loop 4. ClinVar Uncertain significance, AlphaMissense 0.429, DynaMut2 ΔΔG -0.81 kcal/mol (destabilising).

Identity

Field	Value
Variant	A569T (p.Alanine569Threonine)
DNA change	c.1705G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000229639
Amino acid change	Alanine (A) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 569	73.31 — well-folded
Domain	Lumenal loop 4
Position context	C-terminal lumenal domain · position 569 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 569 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 small/hydrophobic (alanine — methyl sidechain); the mutant is small polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4292
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.81 (Destabilising)
Job ID	178094726819
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094726819

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2021/12/22 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A569T 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|=0.81 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.81 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.429. 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
A569T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 569 with ball-and-stick + neighbors within 5Å)
A569T_variant_card.md — this card (source of truth)
A569T_variant_card.html — styled printable card
A569T_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)
A569T_wildtype_interactions.pse / A569T_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 A569T 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 A569T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.