F414L

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Leucine at position 414 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F414 — hydrogen bond to S411

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DynaMut2 mutant · F414L

Mutant L414 — hydrogen bond to S411 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost2 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L410	L410	Preserved
Hydrogen bond	S411	S411	Preserved
Hydrogen bond	S418	S418	Preserved
Polar contact	L410	L410	Preserved
Polar contact	S411	S411	Preserved
Polar contact	V412	V412	Preserved
Polar contact	—	I416	Gained
Polar contact	—	F417	Gained
Polar contact	S418	S418	Preserved
Van der Waals	S411	S411	Preserved
Van der Waals	V412	V412	Preserved
Van der Waals	S418	—	Lost
Hydrophobic	I349	I349	Preserved
Hydrophobic	L410	L410	Preserved
Hydrophobic	L637	—	Lost
Hydrophobic	L640	L640	Preserved
Hydrophobic	T641	—	Lost
Hydrophobic	V644	V644	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

0.31kcal/mol

Stabilising — mild

AlphaMissense

0.933

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 0.00043%

cDNA changec.1242C>A

ClinVar accessionVCV001403366

Last evaluated2021/06/30 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F414L Variant Card

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

Phenylalanine → Leucine at position 414. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.933, DynaMut2 ΔΔG +0.31 kcal/mol (stabilising).

Identity

Field	Value
Variant	F414L (p.Phenylalanine414Leucine)
DNA change	c.1242C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001403366
Amino acid change	Phenylalanine (F) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 414	92.62 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 414 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 414 sits in a transmembrane helix (Transmembrane helix 4). 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	0.9335
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.31 (Stabilising)
Job ID	178092103272
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092103272

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2021/06/30 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	F414L 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|=0.31 < 2 kcal/mol (fold intact) + AlphaMissense 0.933 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|=0.31 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.933. 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
F414L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 414 with ball-and-stick + neighbors within 5Å)
F414L_variant_card.md — this card (source of truth)
F414L_variant_card.html — styled printable card
F414L_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)
F414L_wildtype_interactions.pse / F414L_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 F414L 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 F414L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.