P533S
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialProline → Serine at position 533 inside TM7. ClinVar Conflicting classifications including optic atrophy and DFNA6. AlphaMissense 0.979, DynaMut2 ΔΔG -1.33 kcal/mol (destabilising). Proline-removal in TM7 with substantial structural cost.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Y405 | Y405 | Preserved |
| Hydrogen bond | Y528 | — | Lost |
| Hydrogen bond | C529 | — | Lost |
| Hydrogen bond | Y530 | — | Lost |
| Hydrogen bond | V536 | V536 | Preserved |
| Hydrogen bond | C537 | C537 | Preserved |
| Polar contact | — | Y405 | Gained |
| Polar contact | — | L531 | Gained |
| Polar contact | V536 | V536 | Preserved |
| Polar contact | C537 | C537 | Preserved |
| Hydrophobic | Y405 | — | 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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); Optic atrophy / optic neuropathy (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400); Retinal dystrophy (inheritance not specified). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Retinal dystrophyinheritance not specifiedsubmitted as: Retinal dystrophy
- 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.
Highest in Amish: AF 5.16% (47 of 910 alleles), 46.4x the global figure. The global AF describes the general population, not the at-risk group.
2 homozygotes reported in gnomAD v4 (1 Amish; 1 European (non-Finnish)). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Amish | 5.16% | 47 / 910 | 1 | ~1 in 10 |
| European (non-Finnish) | 0.141% | 1,666 / 1,180,038 | 1 | ~1 in 350 |
| Remaining individuals | 0.066% | 41 / 62,498 | 0 | ~1 in 760 |
| Admixed American | 0.028% | 17 / 60,036 | 0 | ~1 in 1770 |
| South Asian | 0.012% | 11 / 91,084 | 0 | ~1 in 4140 |
| Finnish | 0.0096% | 6 / 62,252 | 0 | ~1 in 5190 |
| African / African American | 0.0067% | 5 / 75,076 | 0 | ~1 in 7510 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,608 | 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 533 sits in TM7 near its start. The AlphaFold model places P533 within 5 Å of TYR534 (2.5 Å), VAL532 (2.5 Å), TYR405 (4.0 Å — TM3-TM7 cross-helix!), TYR530 (4.2 Å), and LEU535 (4.4 Å). The TYR405 contact at 4.0 Å is structurally significant — a TM3-TM7 helix-helix interaction through this proline position.
The wild-type proline at 533 defines TM7's helix-initiation geometry. Removing it eliminates that controlled kink, freeing the backbone. The introduced serine adds a polar hydroxyl into the bilayer-embedded environment, slightly unfavorable.
The |ΔΔG| of 1.33 reflects meaningful fold cost. The TM3-TM7 cross-helix contact at TYR405 is perturbed. AlphaMissense's 0.979 + WFS1-Related Spectrum Disorders + optic atrophy + DFNA6 clinical evidence confirm severe functional consequence across multiple tissue contexts.
Druggability Assessment
Mechanism is loss of TM7 helix-initiation geometry plus disruption of TM3-TM7 cross-helix contact at TYR405. Therapeutic strategy: TM3-TM7 interface site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the P533S 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.