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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 Admixed American: AF 0.030% (18 of 59,974 alleles), 23.0x 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. |
|---|---|---|---|---|
| Admixed American | 0.030% | 18 / 59,974 | 0 | ~1 in 1670 |
| Middle Eastern · under-sampled | 0.016% | 1 / 6,082 | 0 | — |
| European (non-Finnish) | 0.00017% | 2 / 1,179,288 | 0 | ~1 in 294820 |
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 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 does not resolve pathogenicity (ClinVar: conflicting submissions). 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
Feed this card to Wolfram Intelligence
Download the I802M 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.