R558H
Category 3/4 — Most DruggablePathogenic/Likely pathogenicCytoplasmic · predictedEditorialSame residue as the Atlas's R558C pilot variant, different substitution — arginine retained as histidine, a partial charge swap that preserves the side chain's polar character but loses ~80% of the wild-type positive charge at physiological pH.
Reviewed by an affected-family domain expert
The card's structural prose concluded that because R558H lacks R558C's free-thiol oxidative-stress liability, 'clinically, the consequence is that R558H may present with somewhat milder disease.' That is a phenotype claim generalized from a neighbouring variant at the same residue, which the Gladstone review prohibits: structural similarity supports a mechanistic hypothesis, never a phenotype claim. There is no published R558H cohort data on the card to support a severity statement. The mechanistic comparison is retained; the clinical inference is removed and replaced with an explicit statement that presentation does not follow from the structural comparison. Found by an Atlas-wide prose scan while shipping v2 — this was the only instance of cross-variant phenotype generalization in the 2,085-variant corpus.
Dr. Sarah Gladstone · 2026-08-14 · Gladstone v2 policy entry 4 (phenotype generalization)
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E431 | — | Lost |
| Hydrogen bond | E431 | — | Lost |
| Hydrogen bond | L554 | L554 | Preserved |
| Hydrogen bond | G555 | G555 | Preserved |
| Hydrogen bond | G562 | G562 | Preserved |
| Polar contact | E431 | — | Lost |
| Polar contact | L554 | L554 | Preserved |
| Polar contact | G555 | G555 | Preserved |
| Polar contact | G562 | G562 | Preserved |
| Van der Waals | — | L556 | 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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Optic atrophy / optic neuropathy (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related spectrum (unresolved mode) (dominant or recessive). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1; Wolfram syndrome; Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-related disorder
- 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.
Highest in European (non-Finnish): AF 0.0092% (108 of 1,180,042 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) | 0.0092% | 108 / 1,180,042 | 0 | ~1 in 5460 |
| Admixed American | 0.0083% | 5 / 60,014 | 0 | ~1 in 6000 |
| East Asian | 0.0067% | 3 / 44,894 | 0 | ~1 in 7480 |
| South Asian | 0.0044% | 4 / 91,084 | 0 | ~1 in 11390 |
| African / African American | 0.0040% | 3 / 74,946 | 0 | ~1 in 12490 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,470 | 0 | — |
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
R558 sits at the cytoplasmic edge of the membrane interface, 5 residues before the start of TM8. The structural neighbors here are: Ala559 (2.45 Angstrom), Leu557 (2.47 Angstrom), Gly555 (3.63 Angstrom), Leu554 (3.82 Angstrom), Leu556 (4.50 Angstrom), Ser560 (4.61 Angstrom), Ile561 (4.81 Angstrom), and Gly562 (4.90 Angstrom). The cluster is dominated by hydrophobic residues — three leucines, one alanine, one isoleucine, two glycines — and a single polar serine. The wild-type arginine's guanidinium therefore projects outward into solvent or toward an anionic phospholipid headgroup, while its long aliphatic stem packs against the surrounding leucine/alanine cluster.
Replacing arginine with histidine removes the full positive charge but retains a polar imidazole. At cytoplasmic pH (~7.2), histidine is predominantly neutral (~10% protonated). The electrostatic anchor to anionic lipid headgroups is lost. The long aliphatic stem of arginine, which contributes hydrophobic packing against the surrounding leucines, is also lost — histidine's side chain is much shorter (~4 Angstrom vs ~6 Angstrom). The combined effect is geometric: histidine cannot reach the same packing partners as arginine, and the local cluster loses both an electrostatic and a hydrophobic contribution.
DynaMut2's DeltaDeltaG of -1.31 kcal/mol is a clean read of this combined loss — somewhat larger than R558C's -0.5 kcal/mol, consistent with histidine being a more conservative substitution chemically but geometrically more disruptive because of the side-chain length mismatch. AlphaMissense scores R558H at 0.760 (LPath) — pathogenic but notably lower than R558C's 0.849, reflecting the imidazole's partial retention of polar character.
Cross-reference to the R558C pilot card: both variants disrupt the same anchor at the TM7-TM8 cytoplasmic loop. R558C loses the positive charge and adds a free thiol with potential disulfide-formation risk. R558H loses ~90% of the positive charge but adds no covalent-modification liability. The two variants therefore share most of their molecular phenotype but diverge in one respect — R558C carries an additional oxidative-stress vulnerability that R558H does not. That is a mechanistic difference, and it stops there: no clinical inference about R558H's presentation or severity follows from it. Presentation cannot be generalised from a neighbouring variant, even at the same residue — one substitution over can present very differently, and there is no published R558H cohort data on this card to support a severity claim. Both are classified Pathogenic/Likely pathogenic; what that means for a given person is not settled by the structural comparison above. (Corrected 2026-08-21 on expert review — Dr. Sarah Gladstone, 2026-08-14: phenotype generalization across variants.)
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the R558H 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.