L514F

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Leucine → Phenylalanine at position 514 · Transmembrane helix 7 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L514 — hydrogen bond to Y510

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DynaMut2 mutant · L514F

Mutant F514 — hydrogen bond contact to L511 lost

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Bond changes · DynaMut2 interaction analysis

0 lost5 gained16 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	Y454	Gained
Hydrogen bond	Y510	Y510	Preserved
Hydrogen bond	L511	L511	Preserved
Hydrogen bond	R517	R517	Preserved
Hydrogen bond	M518	M518	Preserved
Polar contact	—	Y454	Gained
Polar contact	Y510	Y510	Preserved
Polar contact	L511	L511	Preserved
Polar contact	L512	L512	Preserved
Polar contact	R517	R517	Preserved
Polar contact	M518	M518	Preserved
Aromatic / π	—	Y454	Gained
Aromatic / π	—	Y510	Gained
Van der Waals	—	Y510	Gained
Van der Waals	L511	L511	Preserved
Van der Waals	L512	L512	Preserved
Hydrophobic	Y454	Y454	Preserved
Hydrophobic	R457	R457	Preserved
Hydrophobic	A458	A458	Preserved
Hydrophobic	Y510	Y510	Preserved
Hydrophobic	M518	M518	Preserved

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

-1.32kcal/mol

Destabilising — moderate

AlphaMissense

0.597

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsOptic atrophy; Wolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00043%

cDNA changec.1540C>T

ClinVar accessionVCV001208897

Last evaluated2022/01/01 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — L514F Variant Card

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

Leucine → Phenylalanine at position 514. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.597, DynaMut2 ΔΔG -1.32 kcal/mol (destabilising).

Identity

Field	Value
Variant	L514F (p.Leucine514Phenylalanine)
DNA change	c.1540C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001208897
Amino acid change	Leucine (L) → Phenylalanine (F)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 514	88.12 — well-folded
Domain	Transmembrane helix 7
Position context	Inside Transmembrane helix 7 · position 514 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 514 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 medium hydrophobic (leucine — branched); 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	0.5971
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.32 (Destabilising)
Job ID	178092155662
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092155662

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2022/01/01 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	L514F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Optic atrophy
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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.32 < 2 kcal/mol (fold intact) + AlphaMissense 0.597 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|=1.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.597. 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
L514F_molstar_viewer.html — interactive 3D viewer (auto-highlights position 514 with ball-and-stick + neighbors within 5Å)
L514F_variant_card.md — this card (source of truth)
L514F_variant_card.html — styled printable card
L514F_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)
L514F_wildtype_interactions.pse / L514F_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 L514F 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 L514F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.