A559T

Category 4 — Stable Fold, Function DisruptedLikely benignCytoplasmic · predictedSource card

Alanine → Threonine at position 559 · Lumenal loop 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A559 — hydrogen bond to Y563

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DynaMut2 mutant · A559T

Mutant T559 — hydrogen bond to L556 lost (9 contacts lost)

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Bond changes · DynaMut2 interaction analysis

9 lost4 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	S430	Gained
Hydrogen bond	—	E431	Gained
Hydrogen bond	G555	G555	Preserved
Hydrogen bond	L556	—	Lost
Hydrogen bond	G562	—	Lost
Hydrogen bond	Y563	Y563	Preserved
Polar contact	S430	S430	Preserved
Polar contact	E431	E431	Preserved
Polar contact	—	V434	Gained
Polar contact	G555	G555	Preserved
Polar contact	L556	L556	Preserved
Polar contact	L557	—	Lost
Polar contact	I561	—	Lost
Polar contact	G562	G562	Preserved
Polar contact	Y563	Y563	Preserved
Carbonyl	G562	—	Lost
Van der Waals	E431	—	Lost
Van der Waals	G562	—	Lost
Hydrophobic	E431	—	Lost
Hydrophobic	V434	V434	Preserved
Hydrophobic	—	L556	Gained
Hydrophobic	Y563	—	Lost

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

-1.21kcal/mol

Destabilising — moderate

AlphaMissense

0.352

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationBenign/Likely benign

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWFS1-Related Spectrum Disorders; Monogenic diabetes; Autosomal dominant nonsyndromic hearing loss 6; Wolfram syndrome 1

Population frequency (gnomAD v4)Low frequency · AF 0.485%

cDNA changec.1675G>A

ClinVar accessionVCV000095322

Last evaluated2026/03/01 00:00

Observed in the general population.

Full Variant Card

WFS1 Wolframin — A559T Variant Card

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

Alanine → Threonine at position 559. Lumenal loop 4. ClinVar Benign/Likely benign, AlphaMissense 0.352, DynaMut2 ΔΔG -1.21 kcal/mol (destabilising).

Identity

Field	Value
Variant	A559T (p.Alanine559Threonine)
DNA change	c.1675G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000095322
Amino acid change	Alanine (A) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 559	87.12 — well-folded
Domain	Lumenal loop 4
Position context	C-terminal lumenal domain · position 559 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 559 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	0.3517
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.21 (Destabilising)
Job ID	178094719065
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094719065

Clinical Evidence

Field	Value
Classification	Benign/Likely benign
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/03/01 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A559T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

WFS1-Related Spectrum Disorders
Monogenic diabetes
Autosomal dominant nonsyndromic hearing loss 6
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|=1.21 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.21 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.352. 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
A559T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 559 with ball-and-stick + neighbors within 5Å)
A559T_variant_card.md — this card (source of truth)
A559T_variant_card.html — styled printable card
A559T_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)
A559T_wildtype_interactions.pse / A559T_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 A559T 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 A559T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.