P428R
Category 3/4 — Most DruggablePathogenicTransmembrane · predictedEditorialProline → Arginine at position 428 inside wolframin's fourth transmembrane helix (TM4). ClinVar Pathogenic. AlphaMissense 0.920, DynaMut2 ΔΔG -0.22 kcal/mol (destabilising). A proline-removal variant in a TM helix — opposite mechanism to L543P-type variants.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | E431 | — | Lost |
| Hydrogen bond | L432 | L432 | Preserved |
| Polar contact | Y351 | — | Lost |
| Polar contact | S430 | — | Lost |
| Polar contact | E431 | E431 | Preserved |
| Polar contact | L432 | L432 | Preserved |
| Van der Waals | S430 | — | Lost |
| Van der Waals | L432 | L432 | Preserved |
| Hydrophobic | E431 | E431 | Preserved |
| Hydrophobic | L432 | — | Lost |
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, 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.
Highest in European (non-Finnish): AF 0.00063% (7 of 1,112,012 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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00063% | 7 / 1,112,012 | 0 | ~1 in 79430 |
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 428 sits at the start of TM4. The AlphaFold model places P428 within 5 Å of ILE427 (2.5 Å), CYS429 (2.5 Å), SER430 (4.5 Å), and GLU431 (4.9 Å). The wild-type proline at 428 likely defines the helix-initiation geometry of TM4, providing a controlled bend or break at the start of the membrane-spanning segment.
Replacing proline with arginine has the same backbone-flexibility-gain as P504L (removed proline kink) but with a substantial added complication: a positive charge is introduced near the membrane-water interface. At position 428 — right at the start of TM4 — the arginine side chain can extend toward the lumenal interface where its charge is favorable, but the lost helix-initiation geometry remains a structural problem.
The |ΔΔG| of 0.22 indicates the fold absorbs the substitution. AlphaMissense's 0.920 score captures the functional consequence — TM4's insertion register shifts, the C429 immediately downstream (a possible disulfide-capable residue) is now in a different local geometry, and the E431 contact (4.9 Å) is perturbed.
Notably, the same E431 residue appears as a neighbor in the A559D atlas card — E431 sits between the connecting loop containing R558 and TM4 containing P428. The position is structurally connective in the lumenal-facing region.
Druggability Assessment
The mechanism combines loss of proline-defined helix-initiation geometry plus charge introduction at the membrane-water interface. Therapeutic strategy: site-directed small molecules at the TM4 N-terminal region.
The E431 contact suggests this position may be structurally connected to the R558-E431 microregion that A559D perturbs. Combined drug discovery in both regions has overlapping targets.
Why this matters
Feed this card to Wolfram Intelligence
Download the P428R 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.