F516L

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Leucine at position 516 · Transmembrane helix 7 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F516 — hydrogen bond to Q520

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DynaMut2 mutant · F516L

Mutant L516 — hydrophobic contact to Q520 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L512	L512	Preserved
Hydrogen bond	Y513	Y513	Preserved
Hydrogen bond	A519	A519	Preserved
Hydrogen bond	Q520	Q520	Preserved
Polar contact	L512	L512	Preserved
Polar contact	Y513	Y513	Preserved
Polar contact	A519	A519	Preserved
Polar contact	Q520	Q520	Preserved
Hydrophobic	Q520	—	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

-0.32kcal/mol

Destabilising — mild

AlphaMissense

0.728

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)Ultra-rare · AF 0.000068%

cDNA changec.1546T>C

ClinVar accessionVCV002794872

Last evaluated2023/08/11 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F516L Variant Card

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

Phenylalanine → Leucine at position 516. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.728, DynaMut2 ΔΔG -0.32 kcal/mol (destabilising).

Identity

Field	Value
Variant	F516L (p.Phenylalanine516Leucine)
DNA change	c.1546T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002794872
Amino acid change	Phenylalanine (F) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 516	87.12 — well-folded
Domain	Transmembrane helix 7
Position context	Inside Transmembrane helix 7 · position 516 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 516 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 medium hydrophobic (leucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.7277
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.32 (Destabilising)
Job ID	178092151259
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092151259

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/08/11 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	F516L 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|=0.32 < 2 kcal/mol (fold intact) + AlphaMissense 0.728 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|=0.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.728. 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
F516L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 516 with ball-and-stick + neighbors within 5Å)
F516L_variant_card.md — this card (source of truth)
F516L_variant_card.html — styled printable card
F516L_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)
F516L_wildtype_interactions.pse / F516L_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 F516L 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 F516L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.