S411C

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

Serine → Cysteine at position 411 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S411 — hydrogen bond to F408

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DynaMut2 mutant · S411C

Mutant C411 — hydrogen bond to L637 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost6 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S353	S353	Preserved
Hydrogen bond	S356	—	Lost
Hydrogen bond	—	M357	Gained
Hydrogen bond	H407	H407	Preserved
Hydrogen bond	F408	F408	Preserved
Hydrogen bond	F414	F414	Preserved
Hydrogen bond	V415	V415	Preserved
Hydrogen bond	L637	—	Lost
Polar contact	—	S353	Gained
Polar contact	S356	S356	Preserved
Polar contact	—	M357	Gained
Polar contact	H407	H407	Preserved
Polar contact	F408	F408	Preserved
Polar contact	F413	F413	Preserved
Polar contact	F414	F414	Preserved
Polar contact	V415	V415	Preserved
Van der Waals	S356	—	Lost
Van der Waals	—	F408	Gained
Van der Waals	F413	F413	Preserved
Van der Waals	F414	—	Lost
Hydrophobic	—	M357	Gained
Hydrophobic	—	L637	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

-0.49kcal/mol

Destabilising — mild

AlphaMissense

0.489

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.1232C>G

ClinVar accessionVCV002081723

Last evaluated2022/10/24 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — S411C Variant Card

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

Serine → Cysteine at position 411. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.489, DynaMut2 ΔΔG -0.49 kcal/mol (destabilising).

Identity

Field	Value
Variant	S411C (p.Serine411Cysteine)
DNA change	c.1232C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002081723
Amino acid change	Serine (S) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 411	94.12 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 411 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 411 sits in a transmembrane helix (Transmembrane helix 4). 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 (serine — hydroxyl); the mutant is thiol (cysteine — disulfide-capable, free -SH). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4887
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.49 (Destabilising)
Job ID	178094716506
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094716506

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/10/24 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	S411C 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|=0.49 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.49 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.489. 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
S411C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 411 with ball-and-stick + neighbors within 5Å)
S411C_variant_card.md — this card (source of truth)
S411C_variant_card.html — styled printable card
S411C_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)
S411C_wildtype_interactions.pse / S411C_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 S411C 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 S411C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.