A326T
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialAlanine → Threonine at position 326 inside TM1. ClinVar Conflicting including Wolfram + inborn diseases. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.79. Third substitution at position 326 (with A326E, A326V).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | H322 | H322 | Preserved |
| Hydrogen bond | H323 | H323 | Preserved |
| Hydrogen bond | F329 | F329 | Preserved |
| Hydrogen bond | F330 | F330 | Preserved |
| Polar contact | H322 | H322 | Preserved |
| Polar contact | H323 | H323 | Preserved |
| Polar contact | I324 | I324 | Preserved |
| Polar contact | F329 | F329 | Preserved |
| Polar contact | F330 | F330 | Preserved |
| Van der Waals | — | H322 | Gained |
| Van der Waals | I324 | I324 | Preserved |
| Hydrophobic | F330 | F330 | 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
- 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 Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant). 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.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- 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 0.027% (16 of 59,984 alleles), 4.0x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (1 European (non-Finnish)). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Admixed American | 0.027% | 16 / 59,984 | 0 | ~1 in 1870 |
| Remaining individuals | 0.014% | 9 / 62,482 | 0 | ~1 in 3470 |
| Ashkenazi Jewish | 0.0068% | 2 / 29,606 | 0 | ~1 in 7400 |
| South Asian | 0.0066% | 6 / 91,072 | 0 | ~1 in 7590 |
| European (non-Finnish) | 0.0061% | 72 / 1,179,986 | 1 | ~1 in 8190 |
| African / African American | 0.0040% | 3 / 74,844 | 0 | ~1 in 12470 |
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 326 same neighbors as A326E/A326V: ASN325 (2.5 Å), LEU327 (2.5 Å), HIS322 (3.6 Å).
A326T is the THIRD substitution at position 326 (with A326E charge, A326V volume). Position 326 is structurally inflexible regardless of substitution chemistry — three variants confirm this. AM 0.13 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: polarity introduction at structurally critical TM1 position. Therapeutic: same TM1 microregion as A326E, A326V.
Why this matters
Feed this card to Wolfram Intelligence
Download the A326T 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.