A433P
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialAlanine-to-proline mutation inside transmembrane helix TM4 — a classical helix-breaking substitution that introduces a backbone kink into a structural element that must remain alpha-helical to function as a membrane anchor.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | C429 | C429 | Preserved |
| Hydrogen bond | T436 | T436 | Preserved |
| Hydrogen bond | G437 | G437 | Preserved |
| Polar contact | C429 | C429 | Preserved |
| Polar contact | — | S430 | Gained |
| Polar contact | E431 | — | Lost |
| Polar contact | T436 | T436 | Preserved |
| Polar contact | G437 | G437 | Preserved |
| Van der Waals | C429 | C429 | Preserved |
| Van der Waals | E431 | — | Lost |
| Van der Waals | T436 | T436 | Preserved |
| Hydrophobic | I547 | I547 | Preserved |
| Hydrophobic | L556 | L556 | 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic for Optic atrophy / optic neuropathy (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.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- 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.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
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. |
|---|---|---|---|---|
| South Asian · under-sampled | 0.0012% | 1 / 86,256 | 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
A433 is held between Val434 (2.47 Angstrom) and Leu432 (2.48 Angstrom), with through-space contacts to Thr436 (3.30 Angstrom), Cys429 (3.61 Angstrom), Ile547 (4.04 Angstrom — note: this is far in sequence, indicating an inter-helix contact, likely with TM5), Ser430 (4.10 Angstrom), Glu431 (4.35 Angstrom), and Ile435 (4.42 Angstrom). The contact set tells two stories: a hydrophobic packing core within TM4 itself (Val434, Leu432, Ile435), and an inter-helix interaction with TM5 (Ile547 at 4.04 Angstrom). The wild-type alanine's compact methyl fits cleanly into both contexts.
The Cys429 contact at 3.61 Angstrom is mechanistically important. A free cysteine inside a transmembrane helix at close distance to A433 suggests the wild-type geometry holds the cysteine in a defined orientation. If A433P perturbs that geometry, the cysteine's local environment changes — and a TM-buried cysteine that becomes solvent-accessible or shifts toward an oxidative environment becomes a disulfide-formation liability.
Replacing A433 with proline is one of the most disruptive single-residue substitutions possible inside an alpha-helix. Proline's pyrrolidine ring forces phi near -60 degrees (incompatible with the standard alpha-helix phi of -60 to -65 degrees only when its other constraints are also satisfied — typically not in the middle of an extended helix) and eliminates the backbone amide NH needed for the i-to-i+4 hydrogen bond that defines the alpha-helix structure. Proline insertions in the middle of TM helices reliably introduce 20-30 degree kinks in the helix axis.
The consequence for TM4 is a kink at residue 433 that propagates upward and downward through the helix, shifting the inter-helix register with TM5 (the Ile547 contact at 4.04 Angstrom). The Cys429 environment is also disturbed.
DynaMut2 reports DeltaDeltaG = -0.05 kcal/mol — essentially zero. This is a known limitation of energy functions for proline introductions: the local van der Waals improvement from proline's rigid ring partially compensates the lost hydrogen-bonding capacity, and the energy function under-weighs the structural propagation cost. AlphaMissense at 0.990 reads the true severity: A433P is essentially a TM4 disruption, predicted to be near-fully pathogenic.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the A433P 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.