C541W
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialCysteine → Tryptophan at position 541 inside TM7. ClinVar Conflicting including Wolfram. AlphaMissense 0.657, ΔΔG -1.54.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | E462 | E462 | Preserved |
| Hydrogen bond | C537 | C537 | Preserved |
| Hydrogen bond | F538 | F538 | Preserved |
| Hydrogen bond | S544 | S544 | Preserved |
| Hydrogen bond | V545 | V545 | Preserved |
| Polar contact | T440 | T440 | Preserved |
| Polar contact | E462 | E462 | Preserved |
| Polar contact | C537 | C537 | Preserved |
| Polar contact | F538 | F538 | Preserved |
| Polar contact | L543 | — | Lost |
| Polar contact | S544 | S544 | Preserved |
| Polar contact | V545 | V545 | Preserved |
| Van der Waals | — | E462 | Gained |
| Van der Waals | — | V463 | Gained |
| Van der Waals | S544 | — | Lost |
| Van der Waals | — | V545 | Gained |
| Hydrophobic | T440 | T440 | Preserved |
| Hydrophobic | — | E462 | Gained |
| Hydrophobic | — | V463 | Gained |
| Hydrophobic | — | V545 | Gained |
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 Conflicting classifications of pathogenicity 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
- 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.
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 541 in TM7 (same broader region as L543P, L543F). Neighbors: TRP540 (2.5 Å — adjacent existing tryptophan!), GLU542 (2.5 Å), THR440 (3.4 Å — TM4-TM7 cross-helix!), PHE538 (3.5 Å).
The wild-type C541 is a small thiol in a bilayer-embedded position with aromatic neighbor (W540) and TM4 cross-contact (T440). Replacing it with tryptophan adds massive aromatic volume — creating W540-W541 tandem tryptophan motif. |ΔΔG| 1.54 substantial. AM 0.657 + Wolfram confirm severe consequence.
Druggability Assessment
Mechanism: tandem tryptophan motif creation + TM4-TM7 cross-helix disruption at T440. Therapeutic: TM4-TM7 interface site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the C541W 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.