S368N

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

Serine → Asparagine at position 368 · Lumenal loop 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S368 — hydrogen bond to W371

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DynaMut2 mutant · S368N

Mutant N368 — hydrogen bond contact to F365 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V364	V364	Preserved
Hydrogen bond	F365	F365	Preserved
Hydrogen bond	W371	W371	Preserved
Hydrogen bond	E372	E372	Preserved
Polar contact	V364	V364	Preserved
Polar contact	F365	—	Lost
Polar contact	Q366	Q366	Preserved
Polar contact	W371	W371	Preserved
Polar contact	E372	E372	Preserved
Van der Waals	Q366	Q366	Preserved
Van der Waals	A370	A370	Preserved
Van der Waals	—	W371	Gained

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

-0.48kcal/mol

Destabilising — mild

AlphaMissense

0.373

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance/Uncertain risk allele

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00037%

cDNA changec.1103G>A

ClinVar accessionVCV000045429

Last evaluated2025/01/06 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — S368N Variant Card

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

Serine → Asparagine at position 368. Lumenal loop 1. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.373, DynaMut2 ΔΔG -0.48 kcal/mol (destabilising).

Identity

Field	Value
Variant	S368N (p.Serine368Asparagine)
DNA change	c.1103G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000045429
Amino acid change	Serine (S) → Asparagine (N)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 368	78.94 — well-folded
Domain	Lumenal loop 1
Position context	C-terminal lumenal domain · position 368 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 368 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 polar (serine — hydroxyl); the mutant is polar amide (asparagine — H-bond donor/acceptor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3731
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.48 (Destabilising)
Job ID	178094713618
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094713618

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/01/06 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	S368N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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|=0.48 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.48 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.373. 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
S368N_molstar_viewer.html — interactive 3D viewer (auto-highlights position 368 with ball-and-stick + neighbors within 5Å)
S368N_variant_card.md — this card (source of truth)
S368N_variant_card.html — styled printable card
S368N_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)
S368N_wildtype_interactions.pse / S368N_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 S368N 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 S368N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.