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
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 Hearing loss, inheritance unstated (inheritance not specified).
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Monogenic hearing loss
- 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 European (non-Finnish): AF 0.00027% (3 of 1,111,822 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| Remaining individuals · under-sampled | 0.0017% | 1 / 60,366 | 0 | — |
| South Asian · under-sampled | 0.0012% | 1 / 86,254 | 0 | — |
| European (non-Finnish) | 0.00027% | 3 / 1,111,822 | 0 | ~1 in 185300 |
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 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
Feed this card to Wolfram Intelligence
Download the T699M 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.