R456H
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialArginine → Histidine at position 456 in connecting loop. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.16 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.26 (substantial). Adjacent to R457S.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | E452 | E452 | Preserved |
| Hydrogen bond | A460 | A460 | Preserved |
| Polar contact | E452 | E452 | Preserved |
| Polar contact | A460 | A460 | Preserved |
| Van der Waals | — | A460 | 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
Population frequency too high for a penetrant Wolfram allele — stand-alone benign evidence (ACMG BA1).
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 East Asian: AF 10.06% (4511 of 44,862 alleles), in line with the global figure.
2418 homozygotes reported in gnomAD v4 (235 East Asian; 189 Finnish; 31 Middle Eastern; 245 South Asian; 135 Admixed American; 97 Remaining individuals; 1412 European (non-Finnish); 56 African / African American; 18 Ashkenazi Jewish). 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. |
|---|---|---|---|---|
| East Asian | 10.06% | 4,511 / 44,862 | 235 | ~1 in 5 |
| Finnish | 7.88% | 4,911 / 62,308 | 189 | ~1 in 6 |
| Middle Eastern | 6.95% | 421 / 6,058 | 31 | ~1 in 7 |
| South Asian | 6.37% | 5,799 / 91,066 | 245 | ~1 in 8 |
| Admixed American | 6.09% | 3,653 / 60,018 | 135 | ~1 in 8 |
| Remaining individuals | 5.69% | 3,557 / 62,482 | 97 | ~1 in 9 |
| European (non-Finnish) | 4.81% | 56,709 / 1,179,894 | 1412 | ~1 in 10 |
| African / African American | 3.79% | 2,839 / 74,994 | 56 | ~1 in 13 |
| Ashkenazi Jewish | 3.71% | 1,099 / 29,608 | 18 | ~1 in 13 |
| Amish | 2.64% | 24 / 910 | 0 | ~1 in 19 |
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 456 in connecting loop. Neighbors: ARG457 (2.5 Å — R457S partner!), THR455 (2.5 Å), GLU452 (3.6 Å — likely salt-bridge).
R456H + R457S both at the R456-R457 double-arginine cluster. Partial charge reduction + perturbed E452 salt bridge. |ΔΔG| 1.26 substantial; AM 0.16 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: partial charge loss from R456-R457 cluster + E452 salt-bridge disruption. Therapeutic: same loop as R457S.
Why this matters
Feed this card to Wolfram Intelligence
Download the R456H 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.