L499F
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialLeucine → 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
Bond changes · DynaMut2 interaction analysis
| 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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Optic atrophy / optic neuropathy (autosomal dominant). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- WFS1-related diabetesautosomal dominantsubmitted as: Monogenic diabetes; Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in African / African American: AF 2.40% (1798 of 75,062 alleles), 13.7x the global figure. The global AF describes the general population, not the at-risk group.
21 homozygotes reported in gnomAD v4 (18 African / African American; 1 Admixed American; 1 Middle Eastern; 1 European (non-Finnish)). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| African / African American | 2.40% | 1,798 / 75,062 | 18 | ~1 in 21 |
| Admixed American | 0.273% | 164 / 60,030 | 1 | ~1 in 180 |
| Remaining individuals | 0.259% | 162 / 62,486 | 0 | ~1 in 190 |
| Middle Eastern | 0.181% | 11 / 6,062 | 1 | ~1 in 280 |
| European (non-Finnish) | 0.057% | 668 / 1,180,012 | 1 | ~1 in 880 |
| South Asian | 0.014% | 13 / 91,090 | 0 | ~1 in 3500 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,604 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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.
Druggability Assessment
Mechanism: volume increase in TM6 start. Therapeutic: TM6 cluster (with P504L, C505Y, Y508C, V503G).
Why this matters
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.