T321P
Category 4 — Stable Fold, Function DisruptedLikely pathogenicTransmembrane · predictedEditorialThreonine → Proline at position 321 inside TM1. ClinVar Likely pathogenic. AlphaMissense 0.261 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.13 kcal/mol — essentially neutral. Same position as T321R, proline-introduction at TM1 start.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I319 | — | Lost |
| Hydrogen bond | N325 | N325 | Preserved |
| Polar contact | I319 | I319 | Preserved |
| Polar contact | I324 | — | Lost |
| Polar contact | N325 | N325 | Preserved |
| Van der Waals | — | I319 | Gained |
| Van der Waals | — | N325 | Gained |
| Hydrophobic | I319 | — | Lost |
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 at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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★ single submitter. 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 1,111,994 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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00027% | 3 / 1,111,994 | 0 | ~1 in 185330 |
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 321 sits at the start of TM1. Same neighbor environment as T321R: HIS322 (2.5 Å), PRO320 (2.5 Å — adjacent proline!), ILE319 (3.8 Å), ILE324 (4.4 Å), HIS323 (4.5 Å).
Replacing T321 with proline creates a Pro-Pro motif (P320-P321) in the cytoplasmic-to-TM1 boundary region. Two adjacent prolines produce a rigid backbone segment with restricted conformational options — similar to the L723P/P724S Pro-Pro region in the lumenal domain.
The ΔΔG of +0.13 (essentially neutral) reflects fold accommodation through local rearrangement. AlphaMissense's 0.261 below threshold is AM under-call. ClinVar Likely Pathogenic establishes clinical relevance.
Druggability Assessment
Mechanism is creation of a P320-P321 Pro-Pro motif at the TM1 boundary, altering TM1 insertion geometry. Therapeutic strategy: site-directed at TM1 start.
Why this matters
Feed this card to Wolfram Intelligence
Download the T321P 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.