F515S

Category 2 — Moderately DestabilizingUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Serine at position 515 · Transmembrane helix 7 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F515 — hydrogen bond to A519

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DynaMut2 mutant · F515S

Mutant S515 — polar contact to R517 lost (10 contacts lost)

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Bond changes · DynaMut2 interaction analysis

10 lost0 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L511	L511	Preserved
Hydrogen bond	L512	L512	Preserved
Hydrogen bond	M518	M518	Preserved
Hydrogen bond	A519	A519	Preserved
Polar contact	L511	L511	Preserved
Polar contact	L512	L512	Preserved
Polar contact	Y513	Y513	Preserved
Polar contact	R517	—	Lost
Polar contact	M518	M518	Preserved
Polar contact	A519	A519	Preserved
Aromatic / π	Y534	—	Lost
Van der Waals	L511	—	Lost
Van der Waals	Y513	Y513	Preserved
Van der Waals	R517	—	Lost
Hydrophobic	L511	—	Lost
Hydrophobic	L512	—	Lost
Hydrophobic	M518	—	Lost
Hydrophobic	L531	—	Lost
Hydrophobic	Y534	—	Lost
Hydrophobic	F538	—	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

-3.33kcal/mol

Destabilising — large

AlphaMissense

0.801

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1544T>C

ClinVar accessionVCV002000596

Last evaluated2022/06/28 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F515S Variant Card

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

Phenylalanine → Serine at position 515. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.801, DynaMut2 ΔΔG -3.33 kcal/mol (destabilising).

Identity

Field	Value
Variant	F515S (p.Phenylalanine515Serine)
DNA change	c.1544T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002000596
Amino acid change	Phenylalanine (F) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 515	86.50 — well-folded
Domain	Transmembrane helix 7
Position context	Inside Transmembrane helix 7 · position 515 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 515 sits in a transmembrane helix (Transmembrane helix 7). 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	0.8012
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-3.33 (Destabilising)
Job ID	178092116465
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092116465

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/06/28 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	F515S 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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=3.33 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
F515S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 515 with ball-and-stick + neighbors within 5Å)
F515S_variant_card.md — this card (source of truth)
F515S_variant_card.html — styled printable card
F515S_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)
F515S_wildtype_interactions.pse / F515S_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 F515S 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 F515S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.