I802M
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialIsoleucine → Methionine at position 802 in lumenal domain. ClinVar Conflicting for DFNA6. AlphaMissense 0.35 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.44 kcal/mol (destabilising). Same position as I802T (Cat 2 boundary).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | T778 | — | Lost |
| Hydrogen bond | V779 | V779 | Preserved |
| Hydrogen bond | M781 | — | Lost |
| Hydrogen bond | — | F825 | Gained |
| Polar contact | T778 | — | Lost |
| Polar contact | V779 | V779 | Preserved |
| Van der Waals | M781 | — | Lost |
| Van der Waals | — | F825 | Gained |
| Van der Waals | F840 | — | Lost |
| Hydrophobic | W666 | W666 | Preserved |
| Hydrophobic | W700 | W700 | Preserved |
| Hydrophobic | — | V779 | Gained |
| Hydrophobic | M781 | M781 | Preserved |
| Hydrophobic | L804 | L804 | Preserved |
| Hydrophobic | F825 | F825 | Preserved |
| Hydrophobic | P838 | P838 | Preserved |
| Hydrophobic | F840 | F840 | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 802 same neighbors as I802T: VAL803 (2.4 Å), ASP801 (2.5 Å — partner of D801G), VAL779 (3.9 Å — V779G Cat 2 outlier region!). I802M is the second pathogenic substitution at position 802.
Where I802T introduced polarity (Cat 2 boundary ΔΔG of -1.99), I802M is conservative — flexible sulfur-containing hydrophobic replaces branched aliphatic hydrophobic. The fold absorbs the substitution more easily (|ΔΔG| 0.44).
AlphaMissense's 0.35 is below threshold (AM under-call). DFNA6 clinical evidence confirms pathogenicity. Both I802T and I802M perturb the V779-D801-I802 microregion that connects the V779G Cat 2 outlier to the D801G salt-bridge position.
Druggability Assessment
Mechanism: conservative chemistry shift in the V779-D801-I802 microregion. Therapeutic strategy: same target as I802T, V779G, V779M, D801G, K800E.
Why this matters
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