T699M
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialThreonine → Methionine at position 699 in lumenal domain. ClinVar Conflicting including monogenic hearing loss. AlphaMissense 0.603, ΔΔG +0.01 (neutral). Same position as T699P (Atlas card).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | F825 | F825 | Preserved |
| Polar contact | F825 | F825 | 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 699 same neighbors as T699P: TRP700 (2.4 Å — Cat 2 outlier W700S region), VAL698 (2.5 Å), PHE825 (3.4 Å — W700-F825 π-stacking partner), SER826 (4.3 Å).
T699M is the second pathogenic substitution at 699 (with T699P). Where T699P introduced a backbone kink, T699M conservatively swaps small polar for small hydrophobic. Both perturb the W700-F825 π-stacking geometry that pulls W700S into Cat 2 destabilization.
ΔΔG neutral; AM 0.603 + monogenic hearing loss confirm severe consequence.
Druggability Assessment
Mechanism: W700-F825 π-stacking perturbation via T699 contact. Therapeutic: same W700-F825 microregion as T699P, W700C, W700S.
Why this matters
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