M518I
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialMethionine → Isoleucine at position 518 in a connecting loop. ClinVar carries conflicting classifications across diabetes-related conditions. AlphaMissense 0.966, DynaMut2 ΔΔG -0.29 kcal/mol (destabilising). A conservative hydrophobic substitution whose pathogenicity is mechanism-dependent.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L514 | L514 | Preserved |
| Hydrogen bond | F515 | F515 | Preserved |
| Hydrogen bond | L521 | L521 | Preserved |
| Hydrogen bond | — | G526 | Gained |
| Polar contact | L514 | L514 | Preserved |
| Polar contact | F515 | F515 | Preserved |
| Polar contact | L521 | L521 | Preserved |
| Van der Waals | — | Y454 | Gained |
| Van der Waals | — | Q520 | Gained |
| Van der Waals | — | L521 | Gained |
| Van der Waals | — | L531 | Gained |
| Hydrophobic | Y454 | Y454 | Preserved |
| Hydrophobic | T455 | — | Lost |
| Hydrophobic | A458 | — | Lost |
| Hydrophobic | L514 | — | Lost |
| Hydrophobic | F515 | — | Lost |
| Hydrophobic | — | L521 | Gained |
| Hydrophobic | — | L531 | Gained |
| Hydrophobic | Y534 | Y534 | 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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant); WFS1-related spectrum (unresolved mode) (dominant or recessive). 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 diabetesautosomal dominantsubmitted as: Monogenic diabetes
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- 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 African / African American: AF 0.673% (505 of 75,058 alleles), 18.9x 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. |
|---|---|---|---|---|
| African / African American | 0.673% | 505 / 75,058 | 0 | ~1 in 74 |
| Remaining individuals | 0.064% | 40 / 62,494 | 0 | ~1 in 780 |
| Admixed American | 0.035% | 21 / 60,026 | 0 | ~1 in 1430 |
| Middle Eastern | 0.033% | 2 / 6,062 | 0 | ~1 in 1520 |
| European (non-Finnish) | 0.00051% | 6 / 1,180,014 | 0 | ~1 in 98330 |
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 518 sits in a connecting loop. The AlphaFold model places M518 within 5 Å of ALA519 (2.5 Å), ARG517 (2.5 Å), PHE515 (3.7 Å), LEU514 (3.8 Å), LEU521 (3.9 Å), and GLN520 (4.4 Å). The wild-type methionine's flexible sulfur-containing side chain fits into the surrounding hydrophobic environment (LEU514, LEU521, PHE515) with comparable steric volume to an isoleucine.
Replacing methionine with isoleucine is among the most conservative substitutions chemically — both residues are medium-sized hydrophobic, and isoleucine's branched aliphatic side chain occupies similar volume to methionine's straight-chain thioether. The DynaMut2 |ΔΔG| of 0.29 kcal/mol reflects this conservatism: the fold barely notices the swap.
And yet AlphaMissense calls this pathogenic at 0.966. The mechanism is functional, not structural. Three plausible reasons: first, methionine sulfur can participate in specific protein chemistry that isoleucine cannot — oxidative regulation (Met can be oxidized to Met-sulfoxide as a redox switch), metal coordination, or specific S-mediated interactions; second, methionine residues in certain positions serve as translation initiation alternates or have post-translational modification roles that isoleucine cannot replace; third, the loop's role as a recognition surface depends on the precise methionine geometry, and isoleucine's branched structure presents a different surface even at comparable hydrophobic volume.
The conflicting ClinVar classifications make sense given this profile. Conservative substitutions whose pathogenicity depends on context-specific mechanisms get classified differently by different submitters with different evidence bases.
Druggability Assessment
The mechanism is functional: lost methionine-specific chemistry (oxidative regulation, S-mediated interactions, or surface recognition geometry) that the otherwise-similar isoleucine cannot replace. Therapeutic strategy: site-directed at the loop's functional surface rather than at fold rescue.
This is a variant where the Atlas's dual-metric framing (ΔΔG + AlphaMissense) is essential. Pre-atlas drug discovery focused on destabilizing variants would have missed M518I entirely.
Why this matters
Feed this card to Wolfram Intelligence
Download the M518I 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.