M657L
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialMethionine → Leucine at position 657 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.29. pLDDT 52 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | S654 | S654 | Preserved |
| Hydrogen bond | V659 | V659 | Preserved |
| Hydrogen bond | — | E830 | Gained |
| Polar contact | S654 | S654 | Preserved |
| Polar contact | E655 | E655 | Preserved |
| Polar contact | V659 | V659 | Preserved |
| Carbonyl | E655 | E655 | Preserved |
| Van der Waals | S654 | S654 | Preserved |
| Van der Waals | E655 | E655 | Preserved |
| Hydrophobic | — | V659 | 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
- pLDDT 51.97 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
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 Conflicting classifications of pathogenicity, 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in East Asian: AF 0.056% (25 of 44,882 alleles), 34.6x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| East Asian | 0.056% | 25 / 44,882 | 0 | ~1 in 900 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,482 | 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 657 at lumenal domain start. Neighbors: LYS658 (2.5 Å), GLY656 (2.5 Å), SER654 (3.8 Å). Borderline confidence region.
M657L loses methionine-specific chemistry (oxidative regulation, S-mediated contacts). AM 0.15 under-call; Conflicting evidence.
Druggability Assessment
Mechanism: lost methionine-specific chemistry. Therapeutic: wet-lab validation recommended.
Why this matters
Feed this card to Wolfram Intelligence
Download the M657L 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.