L543F
Category 4 — Stable Fold, Function DisruptedLikely pathogenicTransmembrane · predictedEditorialLeucine → Phenylalanine at position 543 inside TM7. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.303 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.34 kcal/mol (destabilising). Same position as L543P (Atlas card adjacent) but with aromatic introduction.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M539 | M539 | Preserved |
| Hydrogen bond | V546 | V546 | Preserved |
| Hydrogen bond | I547 | I547 | Preserved |
| Polar contact | M539 | M539 | Preserved |
| Polar contact | C541 | C541 | Preserved |
| Polar contact | — | V545 | Gained |
| Polar contact | V546 | V546 | Preserved |
| Polar contact | I547 | I547 | Preserved |
| Aromatic / π | — | F881 | Gained |
| Van der Waals | — | V545 | Gained |
| Van der Waals | I547 | — | Lost |
| Hydrophobic | F354 | — | Lost |
| Hydrophobic | M357 | M357 | Preserved |
| Hydrophobic | — | V412 | Gained |
| Hydrophobic | V415 | V415 | Preserved |
| Hydrophobic | — | I416 | Gained |
| Hydrophobic | T436 | T436 | Preserved |
| Hydrophobic | W540 | — | Lost |
| Hydrophobic | I547 | — | Lost |
| Hydrophobic | F881 | F881 | 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 at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- This rests on a single submitter (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★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,998 | 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 543 sits in TM7. Same neighbor environment as L543P: GLU542 (2.5 Å), SER544 (2.5 Å), MET539 (3.7 Å), TRP540 (3.9 Å), PHE881 (4.1 Å — TM7-TM11 cross-helix).
Replacing L543 with phenylalanine adds aromatic volume to the TM7 mid-helix. Unlike L543P which introduces a backbone kink, L543F preserves α-helical structure but creates a tandem aromatic motif with W540 nearby. The TM7-TM11 cross-helix contact to F881 now involves two phenylalanines in TM7 (F543, with W540 aromatic neighbor) interacting with F881 across the interface.
The |ΔΔG| of 1.34 reflects meaningful fold cost. AlphaMissense's 0.303 below threshold is AM under-call; ClinVar Pathogenic + Wolfram 1 establishes pathogenicity.
Druggability Assessment
Mechanism is aromatic volume mismatch in TM7 plus rearrangement of TM7-TM11 cross-helix contact. Therapeutic strategy: same TM7-TM11 interface as L543P.
Why this matters
Feed this card to Wolfram Intelligence
Download the L543F 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.