T321R
Category 4 — Stable Fold, Function DisruptedLikely pathogenicTransmembrane · predictedEditorialThreonine → Arginine at position 321 inside TM1. ClinVar Likely pathogenic. AlphaMissense 0.449 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.08 kcal/mol — essentially neutral.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I319 | I319 | Preserved |
| Hydrogen bond | N325 | N325 | Preserved |
| Polar contact | I319 | I319 | Preserved |
| Polar contact | I324 | — | Lost |
| Polar contact | N325 | N325 | Preserved |
| 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
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.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
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 in TM1, same neighbor environment as T321P (Atlas card adjacent): HIS322 (2.5 Å — partner of H323R and A326E Atlas cards through the H322-H323-A326 cluster), PRO320 (2.5 Å), ILE319 (3.8 Å), ILE324 (4.4 Å), HIS323 (4.5 Å).
Replacing T321 with arginine introduces a large positive charge into the bilayer-embedded TM1. The arginine side chain likely extends toward the membrane-water interface. The H322-H323 cluster nearby is affected by the new positive charge.
The |ΔΔG| of 0.08 (essentially zero) indicates fold accommodates the substitution. AlphaMissense's 0.449 is below threshold — AM under-call. ClinVar Likely Pathogenic establishes clinical relevance. T321R + T321P (same position, different chemistries) both pathogenic confirm position 321 as functionally important.
Druggability Assessment
Mechanism is charge introduction into TM1. Therapeutic strategy: TM1 microregion site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the T321R 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.