F538S

Category 2 — Moderately DestabilizingLikely risk alleleTransmembrane · predictedSource card

Phenylalanine → Serine at position 538 · Transmembrane helix 8 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F538 — hydrogen bond to Y534

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DynaMut2 mutant · F538S

Mutant S538 — hydrogen bond to E462 lost (10 contacts lost)

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Bond changes · DynaMut2 interaction analysis

10 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E462	—	Lost
Hydrogen bond	Y534	Y534	Preserved
Hydrogen bond	L535	L535	Preserved
Hydrogen bond	C541	C541	Preserved
Hydrogen bond	E542	E542	Preserved
Polar contact	E462	—	Lost
Polar contact	Y534	Y534	Preserved
Polar contact	L535	L535	Preserved
Polar contact	W540	—	Lost
Polar contact	C541	C541	Preserved
Polar contact	E542	E542	Preserved
Van der Waals	E462	—	Lost
Van der Waals	W540	—	Lost
Hydrophobic	E462	—	Lost
Hydrophobic	L511	—	Lost
Hydrophobic	F515	—	Lost
Hydrophobic	Y534	—	Lost
Hydrophobic	E542	—	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

-3.38kcal/mol

Destabilising — large

AlphaMissense

0.984

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationLikely risk allele

Review statuscriteria provided, single submitter

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1613T>C

ClinVar accessionVCV000591231

Last evaluated1/01/01 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — F538S Variant Card

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

Phenylalanine → Serine at position 538. Transmembrane helix 8. ClinVar Likely risk allele, AlphaMissense 0.984, DynaMut2 ΔΔG -3.38 kcal/mol (destabilising).

Identity

Field	Value
Variant	F538S (p.Phenylalanine538Serine)
DNA change	c.1613T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000591231
Amino acid change	Phenylalanine (F) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 538	88.88 — well-folded
Domain	Transmembrane helix 8
Position context	Inside Transmembrane helix 8 · position 538 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 538 sits in a transmembrane helix (Transmembrane helix 8). 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 large aromatic hydrophobic (phenylalanine); 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	0.9842
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-3.38 (Destabilising)
Job ID	178094554004
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094554004

Clinical Evidence

Field	Value
Classification	Likely risk allele
Review status	criteria provided, single submitter
Last evaluated	1/01/01 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	F538S 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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=3.38 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
F538S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 538 with ball-and-stick + neighbors within 5Å)
F538S_variant_card.md — this card (source of truth)
F538S_variant_card.html — styled printable card
F538S_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)
F538S_wildtype_interactions.pse / F538S_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 F538S 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 F538S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.