S353F

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Serine → Phenylalanine at position 353 · Transmembrane helix 2 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S353 — hydrogen bond to M357

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DynaMut2 mutant · S353F

Mutant F353 — hydrogen bond to I349 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost15 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I349	I349	Preserved
Hydrogen bond	F350	F350	Preserved
Hydrogen bond	S356	S356	Preserved
Hydrogen bond	M357	M357	Preserved
Hydrogen bond	S411	S411	Preserved
Polar contact	I349	I349	Preserved
Polar contact	F350	F350	Preserved
Polar contact	—	Y351	Gained
Polar contact	—	I355	Gained
Polar contact	S356	S356	Preserved
Polar contact	M357	M357	Preserved
Polar contact	—	S411	Gained
Polar contact	V415	—	Lost
Aromatic / π	—	F414	Gained
Carbonyl	—	S356	Gained
Van der Waals	I349	—	Lost
Van der Waals	—	F350	Gained
Van der Waals	—	Y351	Gained
Van der Waals	—	S356	Gained
Van der Waals	—	S411	Gained
Van der Waals	—	F414	Gained
Van der Waals	V415	—	Lost
Hydrophobic	—	I349	Gained
Hydrophobic	—	F414	Gained
Hydrophobic	—	V415	Gained
Hydrophobic	—	L637	Gained
Hydrophobic	—	L640	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

-0.58kcal/mol

Destabilising — mild

AlphaMissense

0.983

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Low frequency · AF 0.020%

cDNA changec.1058C>T

ClinVar accessionVCV003720567

Last evaluated2024/03/23 00:00

Observed in the general population.

Full Variant Card

WFS1 Wolframin — S353F Variant Card

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

Serine → Phenylalanine at position 353. Transmembrane helix 2. ClinVar Uncertain significance, AlphaMissense 0.983, DynaMut2 ΔΔG -0.58 kcal/mol (destabilising).

Identity

Field	Value
Variant	S353F (p.Serine353Phenylalanine)
DNA change	c.1058C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003720567
Amino acid change	Serine (S) → Phenylalanine (F)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 353	93.75 — well-folded
Domain	Transmembrane helix 2
Position context	Inside Transmembrane helix 2 · position 353 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 353 sits in a transmembrane helix (Transmembrane helix 2). 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 large aromatic hydrophobic (phenylalanine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9832
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.58 (Destabilising)
Job ID	178092092726
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092092726

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/03/23 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	S353F 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.58 < 2 kcal/mol (fold intact) + AlphaMissense 0.983 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.58 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.983. 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
S353F_molstar_viewer.html — interactive 3D viewer (auto-highlights position 353 with ball-and-stick + neighbors within 5Å)
S353F_variant_card.md — this card (source of truth)
S353F_variant_card.html — styled printable card
S353F_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)
S353F_wildtype_interactions.pse / S353F_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 S353F 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 S353F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.