L543P
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialLeucine → Proline at position 543 inside wolframin's seventh transmembrane helix (TM7). ClinVar Likely pathogenic. AlphaMissense 0.993, DynaMut2 ΔΔG -0.34 kcal/mol (destabilising). A proline-into-TM-helix variant — a structurally severe class of substitution.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M539 | M539 | Preserved |
| Hydrogen bond | V546 | — | Lost |
| Hydrogen bond | I547 | I547 | Preserved |
| Polar contact | M539 | M539 | Preserved |
| Polar contact | C541 | — | Lost |
| Polar contact | — | V545 | Gained |
| Polar contact | V546 | — | Lost |
| Polar contact | I547 | I547 | Preserved |
| Van der Waals | — | M539 | Gained |
| Van der Waals | I547 | — | Lost |
| Hydrophobic | F354 | — | Lost |
| Hydrophobic | M357 | — | Lost |
| Hydrophobic | V415 | — | Lost |
| Hydrophobic | T436 | — | Lost |
| Hydrophobic | W540 | — | Lost |
| Hydrophobic | I547 | I547 | Preserved |
| 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
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 the middle of TM7, one of wolframin's eleven transmembrane helices. The AlphaFold model places L543 within 5 Å of GLU542 (2.5 Å), SER544 (2.5 Å), MET539 (3.7 Å), TRP540 (3.9 Å), PHE881 (4.1 Å, from TM11 — TM7-TM11 cross-helix contact), and CYS541 (4.3 Å). The wild-type leucine fits cleanly into this position, contributing branched hydrophobic packing into TM7's helical structure and into the TM7-TM11 helix-helix interface.
Replacing leucine with proline in the middle of a transmembrane helix is one of the more disruptive substitutions in protein chemistry. Proline's backbone is locked into a five-membered ring; its phi angle is constrained to roughly -60°; it cannot serve as a hydrogen-bond donor in the backbone amide network that holds α-helices together. When proline is introduced into the middle of a helix, the helix either kinks at that position or partially unwinds — neither outcome is consistent with the wild-type membrane-spanning geometry.
DynaMut2 returns a modest |ΔΔG| of 0.34 kcal/mol. This understates the structural cost. The model captures local rearrangement but does not fully simulate the consequence of breaking an α-helix in the middle of a bilayer-spanning segment: TM7's ability to traverse the membrane in its wild-type orientation is compromised, and the lost packing against PHE881 in TM11 perturbs the relative geometry of two helices simultaneously.
AlphaMissense's score of 0.993 captures this severity. The variant is pathogenic by mechanism — broken TM7 geometry, disrupted TM7-TM11 interface — rather than by global misfolding.
Druggability Assessment
The mechanism is helix integrity disruption inside TM7 plus loss of the TM7-TM11 cross-helix packing at the PHE881 contact. This is the same TM-TM interface vocabulary used elsewhere in the Atlas (TM3-TM10 at PHE414, TM6-TM11 at PRO885) but with proline-induced helix breakage as the perturbation mechanism rather than charge or volume mismatch.
Therapeutic strategy: a small molecule that stabilizes TM7's helical register through the position 542-544 region, ideally engaging both TM7 and TM11 across the helix interface. Pharmacological chaperone screening with a focus on TM helix stabilization is a plausible secondary track.
Why this matters
Feed this card to Wolfram Intelligence
Download the L543P 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.