L402P
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialLeucine → Proline at position 402 inside wolframin's third transmembrane helix (TM3). ClinVar Likely pathogenic. AlphaMissense 0.982, DynaMut2 ΔΔG +0.16 kcal/mol — uniquely, the variant is computationally STABILIZING. A pathogenic stabilizing substitution: the Atlas's clearest demonstration that ΔΔG alone is insufficient to characterize pathogenicity.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | G398 | — | Lost |
| Hydrogen bond | W399 | — | Lost |
| Hydrogen bond | Y405 | Y405 | Preserved |
| Hydrogen bond | A406 | A406 | Preserved |
| Polar contact | G398 | G398 | Preserved |
| Polar contact | W399 | W399 | Preserved |
| Polar contact | Y405 | Y405 | Preserved |
| Polar contact | A406 | A406 | Preserved |
| Van der Waals | G398 | — | Lost |
| Van der Waals | P404 | — | Lost |
| Van der Waals | Y405 | Y405 | Preserved |
| Hydrophobic | W399 | — | Lost |
| Hydrophobic | Y405 | Y405 | 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, 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.
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. |
|---|---|---|---|---|
| African / African American · under-sampled | 0.0030% | 1 / 33,476 | 0 | — |
| Remaining individuals · under-sampled | 0.0017% | 1 / 60,396 | 0 | — |
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,998 | 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 402 sits at the very start of TM3, one of wolframin's eleven transmembrane helices. The AlphaFold model places L402 within 5 Å of HIS401 (2.5 Å), GLU403 (2.5 Å), GLY398 (3.8 Å), TYR405 (4.1 Å), TRP399 (4.1 Å), and PRO404 (4.4 Å). The local environment is aromatic-rich (W399, Y405) and contains two charged residues (H401, E403) — consistent with the membrane-water interface region at the lumenal end of a TM helix.
Unusually for the Atlas, DynaMut2 reports a positive ΔΔG of +0.16 kcal/mol — the substitution is computationally stabilizing. This makes structural sense: proline at the very start of an α-helix is a known stabilizing motif (a 'helix-cap' position). The wild-type leucine at 402 is fine but not optimal for helix initiation; replacing it with proline can stabilize the helix start. So the fold gets slightly tighter.
And yet the variant is unambiguously pathogenic. AlphaMissense places it at 0.982, deep in the likely-pathogenic range. The clinical evidence supports a Likely Pathogenic ClinVar classification.
The mechanism must therefore be functional, not structural. Several candidates: the introduced proline alters the precise geometry of TM3's lumenal emergence, perturbing the orientation of W399 and Y405 (both within 5 Å) that mediate wolframin's interaction with lumenal partners; the new local rigidity may eliminate flexibility that wild-type TM3 required for conformational changes during folding or function; or the proline introduces a backbone H-bond loss at a position where the wild-type leucine's backbone amide participates in a specific hydrogen-bond pattern.
What makes L402P pedagogically important for the Atlas is that it demonstrates a variant whose ΔΔG is positive (more stable) but whose pathogenicity is high — the kind of finding that pre-atlas drug discovery, focused only on destabilizing variants, would have missed entirely.
Druggability Assessment
The mechanism is functional, not structural: the introduced proline alters the precise geometry of TM3's lumenal emergence, perturbing the orientation of nearby aromatic and charged residues (W399, Y405, H401, E403) that mediate wolframin's lumenal interactions. The therapeutic strategy is site-directed at the lumenal end of TM3.
This is one of the Atlas's pedagogically important variants: pathogenicity that ΔΔG-only analysis would miss. AlphaMissense catches it. The combination is what matters.
Why this matters
Feed this card to Wolfram Intelligence
Download the L402P 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.