A326E
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialAlanine → Glutamate at position 326 inside TM1. ClinVar Likely pathogenic, DFNA6 hearing loss. AlphaMissense 0.940, DynaMut2 ΔΔG -0.33 kcal/mol (destabilising). Charge-introduction variant in TM1.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | H322 | H322 | Preserved |
| Hydrogen bond | H323 | — | Lost |
| 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 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Likely pathogenic for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- This rests on a single submitter (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★ 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 326 sits in TM1. The AlphaFold model places A326 within 5 Å of ASN325 (2.5 Å), LEU327 (2.5 Å), HIS322 (3.6 Å), HIS323 (3.7 Å — partner of H323R Atlas card), and PHE329 (4.2 Å). The local environment includes two adjacent histidines (H322, H323).
Replacing alanine with glutamate introduces a negative charge into the bilayer-embedded TM1 environment. The carboxylate can interact with the nearby H322/H323 imidazoles when they're protonated, potentially forming a stable salt-bridge that differs from the wild-type fold geometry. But this rearrangement comes at a structural cost.
The |ΔΔG| of 0.33 reflects fold accommodation. AlphaMissense's 0.940 + DFNA6 confirm severe functional consequence. Mechanism is charge introduction at the TM1 H322-H323 cluster.
Druggability Assessment
Mechanism is charge introduction into the TM1 H322-H323 cluster. Therapeutic strategy: site-directed at TM1 mid-helix.
Why this matters
Feed this card to Wolfram Intelligence
Download the A326E 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.