T378S

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

Threonine → Serine at position 378 · Transmembrane helix 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T378 — hydrogen bond to L382

Fullscreen ↗

DynaMut2 mutant · T378S

Mutant S378 — hydrogen bond to R375 lost (3 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

3 lost3 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F374	F374	Preserved
Hydrogen bond	R375	R375	Preserved
Hydrogen bond	L381	—	Lost
Hydrogen bond	L382	L382	Preserved
Hydrogen bond	—	V390	Gained
Polar contact	F374	F374	Preserved
Polar contact	R375	R375	Preserved
Polar contact	L380	—	Lost
Polar contact	L381	L381	Preserved
Polar contact	L382	L382	Preserved
Polar contact	—	V390	Gained
Van der Waals	L380	L380	Preserved
Van der Waals	—	V390	Gained
Hydrophobic	F374	—	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

-0.57kcal/mol

Destabilising — mild

AlphaMissense

0.558

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 0.000068%

cDNA changec.1132A>T

ClinVar accessionVCV002963127

Last evaluated2023/11/27 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — T378S Variant Card

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

Threonine → Serine at position 378. Transmembrane helix 3. ClinVar Uncertain significance, AlphaMissense 0.558, DynaMut2 ΔΔG -0.57 kcal/mol (destabilising).

Identity

Field	Value
Variant	T378S (p.Threonine378Serine)
DNA change	c.1132A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002963127
Amino acid change	Threonine (T) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 378	85.06 — well-folded
Domain	Transmembrane helix 3
Position context	Inside Transmembrane helix 3 · position 378 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 378 sits in a transmembrane helix (Transmembrane helix 3). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. 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	0.5578
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.57 (Destabilising)
Job ID	178094711158
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094711158

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/11/27 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	T378S 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|=0.57 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.57 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.558. 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
T378S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 378 with ball-and-stick + neighbors within 5Å)
T378S_variant_card.md — this card (source of truth)
T378S_variant_card.html — styled printable card
T378S_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)
T378S_wildtype_interactions.pse / T378S_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 T378S 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 T378S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.