C505Y
Category 3/4 — Most DruggablePathogenicTransmembrane · predictedEditorialCysteine → Tyrosine at position 505 inside wolframin's sixth transmembrane helix (TM6). ClinVar Pathogenic, associated with diabetes mellitus. AlphaMissense 0.892 (deep pathogenic range), DynaMut2 ΔΔG -0.81 kcal/mol (destabilising). A bilayer-embedded variant with a TM6-TM11 cross-helix mechanism.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | S502 | S502 | Preserved |
| Hydrogen bond | Y508 | Y508 | Preserved |
| Hydrogen bond | V509 | V509 | Preserved |
| Hydrogen bond | F886 | — | Lost |
| Polar contact | — | T487 | Gained |
| Polar contact | N500 | N500 | Preserved |
| Polar contact | S502 | S502 | Preserved |
| Polar contact | V503 | V503 | Preserved |
| Polar contact | L507 | — | Lost |
| Polar contact | Y508 | — | Lost |
| Polar contact | V509 | V509 | Preserved |
| Polar contact | — | P885 | Gained |
| Van der Waals | — | N500 | Gained |
| Van der Waals | S502 | — | Lost |
| Van der Waals | L507 | — | Lost |
| Van der Waals | F886 | — | Lost |
| Hydrophobic | — | T487 | Gained |
| Hydrophobic | — | N500 | Gained |
| Hydrophobic | — | P885 | 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic for WFS1-related diabetes (autosomal dominant). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- WFS1-related diabetesautosomal dominantsubmitted as: Diabetes mellitus
- No assertion criteria were provided (0★). Treat the conditions above as unverified submissions, 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: 0★ no assertion criteria provided. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00036% (4 of 1,111,982 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| African / African American · under-sampled | 0.0030% | 1 / 33,478 | 0 | — |
| European (non-Finnish) | 0.00036% | 4 / 1,111,982 | 0 | ~1 in 139000 |
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 505 sits inside TM6, one of wolframin's eleven transmembrane helices. The AlphaFold model places C505 within 5 Å of PRO504 (2.5 Å), LEU506 (2.5 Å), SER502 (3.6 Å), PRO885 (4.1 Å), VAL503 (4.2 Å), and TYR508 (4.3 Å). The most structurally significant neighbor is PRO885 — that's a residue from TM11 (Atlas card P885L adjacent), positioned 4.1 Å away in the AlphaFold structure. This contact indicates that TM6 and TM11 cross each other in the membrane and pack against one another through the C505/P885 region.
The wild-type cysteine at position 505 is small and hydrophobic-character — its thiol can either remain free or, in oxidizing conditions, participate in disulfide formation. The local environment here is bilayer-embedded so disulfide formation is not the dominant mechanism. The wild-type's small volume fits cleanly into the TM6-TM11 packing interface.
Replacing cysteine with tyrosine here is unusually disruptive for two reasons. First, the volume increase: tyrosine's aromatic ring is roughly four times the side-chain mass of cysteine. The TM6-TM11 interface, which packs tightly through the C505/P885 region, cannot accommodate the larger side chain without significant rearrangement. Second, the introduced hydroxyl is unfavorable in the bilayer hydrophobic core — it would prefer to point toward the membrane-water interface, dragging the local geometry with it.
DynaMut2's |ΔΔG| of 0.81 kcal/mol captures the modest energetic cost of the fold absorbing this rearrangement. But the functional consequence — disrupted TM6-TM11 packing — is more severe than the ΔΔG alone suggests. AlphaMissense's 0.892 score reflects this. Compare with P504L (Atlas card adjacent): proline at position 504 plays a deliberate helix-kinking role, and removing it has its own structural cost. The two variants together — C505Y and P504L — characterize a vulnerable region in TM6 where multiple substitutions produce convergent functional disruption.
Druggability Assessment
The mechanism is disrupted TM6-TM11 helix-helix packing through the C505-P885 contact (4.1 Å in the AlphaFold model). The atlas-surfaced cross-helix interaction makes the therapeutic target geometric: a small molecule that stabilizes the TM6-TM11 interface, occupying the steric niche the wild-type cysteine maintained, would compensate.
The reciprocal Atlas card (P885L) shows the same interface from the TM11 side. Drug discovery targeting this interface has two converging mechanisms it could rescue simultaneously.
Why this matters
Feed this card to Wolfram Intelligence
Download the C505Y 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.