F413V

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Phenylalanine → Valine at position 413 · TM3 (402-422), helical transmembrane · WFS1 (Wolframin)

Phe→Val p413 TM3 AM=0.05 ddg=-0.42 pLDDT=92. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type F413 — hydrogen bond to L409

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DynaMut2 mutant · F413V

Mutant V413 — polar contact to L410 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost2 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L409	L409	Preserved
Hydrogen bond	L410	L410	Preserved
Hydrogen bond	F417	F417	Preserved
Polar contact	L409	L409	Preserved
Polar contact	L410	L410	Preserved
Polar contact	S411	S411	Preserved
Polar contact	V415	—	Lost
Polar contact	I416	I416	Preserved
Polar contact	F417	F417	Preserved
Aromatic / π	F417	—	Lost
Van der Waals	—	L409	Gained
Van der Waals	S411	S411	Preserved
Van der Waals	—	F417	Gained
Hydrophobic	F417	F417	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

-0.42kcal/mol

Destabilising — mild

AlphaMissense

0.055

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditions(no specific conditions catalogued)

InheritanceConflicting ClinVar classifications.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0062%

cDNA changec.1237T>G

ClinVar accessionVCV000166584

Last evaluated2026/01/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: VAL412 (2.5 Å — V412L/V412A!), PHE414 (2.5 Å — adjacent existing F, also TM3-TM10 contact partner of T641K!), LEU410 (3.8 Å). Multi-variant TM3 cluster. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

aromatic loss + volume reduction

Position in the protein

TM3 (402-422)

Druggability Assessment

Cat 3/4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

Why this matters

TM3 cluster (V412L/A + F413V) — also F414 connects to TM10 T641K.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the F413V 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 F413V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane402–422 · Helical