L499F

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Leucine → Phenylalanine at position 499 · TM6 (496-516), helical transmembrane · WFS1 (Wolframin)

Leucine → Phenylalanine at position 499 inside TM6. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.11 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.62.

Interactive 3D Structure

Wild-type reference

Wild-type L499 — hydrogen bond to V491

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DynaMut2 mutant · L499F

Mutant F499 — hydrogen bond to F886 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost3 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T490	T490	Preserved
Hydrogen bond	V491	V491	Preserved
Hydrogen bond	F886	F886	Preserved
Polar contact	T490	—	Lost
Polar contact	V491	V491	Preserved
Polar contact	—	F886	Gained
Aromatic / π	—	F886	Gained
Carbonyl	T490	—	Lost
Hydrophobic	V491	V491	Preserved
Hydrophobic	V493	V493	Preserved
Hydrophobic	—	V501	Gained
Hydrophobic	F886	F886	Preserved
Hydrophobic	L887	L887	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

-0.62kcal/mol

Destabilising — mild

AlphaMissense

0.106

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 conditionsWFS1-Related Spectrum Disorders; Monogenic diabetes

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Low frequency · AF 0.175%

cDNA changec.1495C>T

ClinVar accessionVCV000045436

Last evaluated2026/01/27 00:00

Observed in the general population.

Structural Context

Position 499 in TM6 near start. Neighbors: ASN500 (2.4 Å), VAL498 (2.5 Å), VAL491 (3.6 Å). Conservative aliphatic environment.

L499F introduces aromatic volume in TM6. AM 0.11 under-call; multi-phenotype confirms.

Amino-acid chemistry

Leucine (L) → Phenylalanine (F) — branched aliphatic to aromatic. Volume increase + aromatic introduction.

Position in the protein

TM6 (residues 496–516) · position 499 near TM6 start (pLDDT 81).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.62. AlphaMissense 0.11 below threshold but multi-phenotype confirms.

Mechanism: volume increase in TM6 start. Therapeutic: TM6 cluster (with P504L, C505Y, Y508C, V503G).

Why this matters

L499F extends TM6 multi-variant cluster — six variants now converge on TM6 mid-helix region.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L499F 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 L499F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane496–516 · Helical