T337A

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

Threonine → Alanine at position 337 · Cytoplasmic loop 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T337 — hydrogen bond to N335

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DynaMut2 mutant · T337A

Mutant A337 — hydrogen bond contact to F340 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	N335	N335	Preserved
Hydrogen bond	F340	F340	Preserved
Hydrogen bond	F341	F341	Preserved
Polar contact	N335	N335	Preserved
Polar contact	D339	D339	Preserved
Polar contact	F340	F340	Preserved
Polar contact	F341	F341	Preserved
Van der Waals	—	N335	Gained
Van der Waals	—	D339	Gained
Van der Waals	F340	—	Lost
Van der Waals	F341	F341	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

-0.26kcal/mol

Destabilising — mild

AlphaMissense

0.361

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1009A>G

ClinVar accessionVCV002133735

Last evaluated2022/05/04 00:00

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

Full Variant Card

WFS1 Wolframin — T337A Variant Card

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

Threonine → Alanine at position 337. Cytoplasmic loop 1. ClinVar Uncertain significance, AlphaMissense 0.361, DynaMut2 ΔΔG -0.26 kcal/mol (destabilising).

Identity

Field	Value
Variant	T337A (p.Threonine337Alanine)
DNA change	c.1009A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002133735
Amino acid change	Threonine (T) → Alanine (A)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 337	65.12 — confident
Domain	Cytoplasmic loop 1
Position context	Loop region · position 337 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 337 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 polar (threonine — hydroxyl); the mutant is small/hydrophobic (alanine — methyl sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3606
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.26 (Destabilising)
Job ID	178094719777
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094719777

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/05/04 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	T337A 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.26 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.26 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.361. 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
T337A_molstar_viewer.html — interactive 3D viewer (auto-highlights position 337 with ball-and-stick + neighbors within 5Å)
T337A_variant_card.md — this card (source of truth)
T337A_variant_card.html — styled printable card
T337A_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)
T337A_wildtype_interactions.pse / T337A_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 T337A 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 T337A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.