A519T

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Alanine → Threonine at position 519 · Cytoplasmic loop 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A519 — hydrogen bond to F515

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DynaMut2 mutant · A519T

Mutant T519 — van der waals to L521 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost5 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F515	F515	Preserved
Hydrogen bond	F516	F516	Preserved
Hydrogen bond	F524	F524	Preserved
Hydrogen bond	—	L531	Gained
Polar contact	F515	F515	Preserved
Polar contact	F516	F516	Preserved
Polar contact	L521	L521	Preserved
Polar contact	F524	F524	Preserved
Polar contact	—	L531	Gained
Van der Waals	—	F516	Gained
Van der Waals	R517	R517	Preserved
Van der Waals	L521	—	Lost
Van der Waals	—	L531	Gained
Hydrophobic	—	F524	Gained
Hydrophobic	T527	T527	Preserved
Hydrophobic	L531	—	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

-1.87kcal/mol

Destabilising — moderate

AlphaMissense

0.755

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

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1555G>A

ClinVar accessionVCV003590700

Last evaluated2024/04/29 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — A519T Variant Card

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

Alanine → Threonine at position 519. Cytoplasmic loop 4. ClinVar Uncertain significance, AlphaMissense 0.755, DynaMut2 ΔΔG -1.87 kcal/mol (destabilising).

Identity

Field	Value
Variant	A519T (p.Alanine519Threonine)
DNA change	c.1555G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590700
Amino acid change	Alanine (A) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 519	85.12 — well-folded
Domain	Cytoplasmic loop 4
Position context	Loop region · position 519 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 519 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 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	0.7551
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.87 (Destabilising)
Job ID	178092120904
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092120904

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/04/29 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A519T 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 syndrome 1
Wolfram-like syndrome
Type 2 diabetes mellitus

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|=1.87 < 2 kcal/mol (fold intact) + AlphaMissense 0.755 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|=1.87 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.755. 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
A519T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 519 with ball-and-stick + neighbors within 5Å)
A519T_variant_card.md — this card (source of truth)
A519T_variant_card.html — styled printable card
A519T_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)
A519T_wildtype_interactions.pse / A519T_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 A519T 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 A519T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.