R868H
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArginine → Histidine at position 868 near the lumenal C-terminus. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.19 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.72. pLDDT 68 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | H872 | H872 | Preserved |
| Polar contact | D866 | D866 | Preserved |
| Polar contact | H872 | H872 | Preserved |
| Aromatic / π | — | H872 | Gained |
| Van der Waals | D866 | D866 | Preserved |
| Van der Waals | T870 | — | Lost |
| Van der Waals | H872 | H872 | 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
- pLDDT 67.62 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
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 WFS1-related spectrum (unresolved mode) (dominant or recessive); 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). 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.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; 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
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Also submitted under Autistic behavior — outside the established WFS1 phenotype families; recorded here as a submission, not presented as a WFS1 phenotype.
- 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 Middle Eastern: AF 0.049% (3 of 6,084 alleles), 6.4x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Middle Eastern | 0.049% | 3 / 6,084 | 0 | ~1 in 1010 |
| South Asian | 0.021% | 19 / 91,086 | 0 | ~1 in 2400 |
| Remaining individuals | 0.014% | 9 / 62,476 | 0 | ~1 in 3470 |
| East Asian | 0.011% | 5 / 44,886 | 0 | ~1 in 4490 |
| European (non-Finnish) | 0.0069% | 82 / 1,180,046 | 0 | ~1 in 7200 |
| African / African American | 0.0067% | 5 / 74,944 | 0 | ~1 in 7490 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,600 | 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
Position 868 near C-terminus. Neighbors: SER869 (2.5 Å), TRP867 (2.5 Å — W867 in TM11 cluster), ASP866 (4.0 Å — D866N region).
R868H sits in the dense 866-876 C-terminal microregion (with D866N, K876T, K862N, E864K). Partial charge loss + perturbed D866 salt-bridge contact. AM 0.19 under-call; multi-phenotype does not resolve it (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: partial charge loss in C-terminal multi-variant cluster. Therapeutic: same 866-876 microregion as D866N, K862N, E864K, K876T.
Why this matters
Feed this card to Wolfram Intelligence
Download the R868H 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.