T461S

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

Threonine → Serine at position 461 · Cytoplasmic loop 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T461 — hydrogen bond to R457

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DynaMut2 mutant · T461S

Mutant S461 — hydrogen bond to R457 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost4 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R457	R457	Preserved
Hydrogen bond	A458	A458	Preserved
Hydrogen bond	T464	T464	Preserved
Hydrogen bond	A465	A465	Preserved
Hydrogen bond	—	Y510	Gained
Polar contact	R457	R457	Preserved
Polar contact	A458	A458	Preserved
Polar contact	L459	L459	Preserved
Polar contact	—	T464	Gained
Polar contact	A465	A465	Preserved
Polar contact	—	Y510	Gained
Van der Waals	—	R457	Gained
Van der Waals	A458	A458	Preserved
Van der Waals	L459	L459	Preserved
Van der Waals	A465	A465	Preserved
Van der Waals	Y510	—	Lost
Hydrophobic	Y510	—	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

-1.04kcal/mol

Destabilising — moderate

AlphaMissense

0.341

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)Ultra-rare · AF 0.00027%

cDNA changec.1381A>T

ClinVar accessionVCV003705860

Last evaluated2024/04/14 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — T461S Variant Card

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

Threonine → Serine at position 461. Cytoplasmic loop 3. ClinVar Uncertain significance, AlphaMissense 0.341, DynaMut2 ΔΔG -1.04 kcal/mol (destabilising).

Identity

Field	Value
Variant	T461S (p.Threonine461Serine)
DNA change	c.1381A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003705860
Amino acid change	Threonine (T) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 461	86.12 — well-folded
Domain	Cytoplasmic loop 3
Position context	Loop region · position 461 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 461 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 polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3405
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.04 (Destabilising)
Job ID	178094707067
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094707067

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/04/14 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	T461S 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|=1.04 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.04 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.341. 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
T461S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 461 with ball-and-stick + neighbors within 5Å)
T461S_variant_card.md — this card (source of truth)
T461S_variant_card.html — styled printable card
T461S_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)
T461S_wildtype_interactions.pse / T461S_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 T461S 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 T461S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.