H323R
Category 3/4 — Most DruggablePathogenic/Likely pathogenicTransmembrane · predictedEditorialHistidine-to-arginine swap inside transmembrane helix TM1 — partial-charge histidine replaced by full-charge arginine in the bilayer environment, with mild predicted DeltaDeltaG that does not capture the membrane desolvation penalty.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P320 | P320 | Preserved |
| Hydrogen bond | A326 | A326 | Preserved |
| Hydrogen bond | L327 | L327 | Preserved |
| Polar contact | P320 | P320 | Preserved |
| Polar contact | A326 | A326 | Preserved |
| Polar contact | L327 | L327 | Preserved |
| Van der Waals | — | P320 | Gained |
| Hydrophobic | P320 | P320 | Preserved |
| Hydrophobic | — | L327 | Gained |
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 Pathogenic/Likely pathogenic for Optic atrophy / optic neuropathy (autosomal dominant). 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.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- 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: 2★ multiple submitters, no conflicts. 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
H323 is held between His322 (2.45 Angstrom) and Ile324 (2.46 Angstrom) covalently. Through-space neighbors read Pro320 (3.53 Angstrom), Ala326 (4.25 Angstrom), Thr321 (4.49 Angstrom), Asn325 (4.49 Angstrom), and Leu327 (4.93 Angstrom). The pair of adjacent histidines at 322-323 is structurally distinctive: two imidazole side chains separated by a single peptide bond, both within a transmembrane helix. The wild-type arrangement likely places both imidazoles facing inward toward each other or coordinating with the polar Thr321 and Asn325, forming a small polar cluster within the helix interior.
Replacing H323 with arginine introduces a fully charged guanidinium where a partial-charge imidazole sat. The thermodynamic problem is desolvation: arginine in a bilayer interior carries a desolvation cost of 8-12 kcal/mol if fully buried, less if its side chain can snorkel toward an interfacial water network. The presence of nearby polar residues (Thr321, Asn325, the H322 imidazole) provides some partial solvation, but the local geometry was not built to host a permanently charged residue.
The structural consequence is one of two outcomes: either Arg323's guanidinium snorkels toward the cytoplasmic face of TM1 (potentially dragging the helix slightly out of register), or it remains buried at substantial energetic cost. Either outcome perturbs TM1 packing against its neighboring helices.
DynaMut2's DeltaDeltaG of -0.02 kcal/mol — essentially zero — is a known weakness of energy functions for buried charge substitutions. The function captures local van der Waals and hydrogen-bond changes but under-weights desolvation. AlphaMissense at 0.687 is closer to a true read of the disruption: clearly pathogenic (above the 0.564 threshold) but not the highest-scoring variant in this batch, consistent with the imidazole-to-guanidinium swap being chemically less drastic than e.g. a glycine-to-arginine substitution.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the H323R 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.