R457S
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialArginine → Serine at position 457 in connecting loop. ClinVar Conflicting including monogenic diabetes + spastic. AlphaMissense 0.515 (borderline), ΔΔG -0.82.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P453 | P453 | Preserved |
| Hydrogen bond | Y454 | Y454 | Preserved |
| Hydrogen bond | A460 | A460 | Preserved |
| Hydrogen bond | T461 | T461 | Preserved |
| Polar contact | P453 | P453 | Preserved |
| Polar contact | Y454 | Y454 | Preserved |
| Polar contact | — | T455 | Gained |
| Polar contact | A460 | A460 | Preserved |
| Polar contact | T461 | T461 | Preserved |
| Polar contact | — | L514 | Gained |
| Hydrophobic | L514 | — | Lost |
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
Observed in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); WFS1-related diabetes (autosomal dominant); Ataxia / spastic ataxia (inheritance not specified); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Hearing loss, inheritance unstated (inheritance not specified). 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 disorder; WFS1-Related Spectrum Disorders
- WFS1-related diabetesautosomal dominantsubmitted as: Monogenic diabetes; Type 2 diabetes mellitus
- Ataxia / spastic ataxiainheritance not specifiedsubmitted as: Spastic ataxia
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: 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
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Hearing impairment
- 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 European (non-Finnish): AF 0.061% (720 of 1,179,846 alleles), in line with the global figure.
2 homozygotes reported in gnomAD v4 (2 European (non-Finnish)). 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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.061% | 720 / 1,179,846 | 2 | ~1 in 820 |
| Remaining individuals | 0.037% | 23 / 62,484 | 0 | ~1 in 1360 |
| African / African American | 0.015% | 11 / 75,038 | 0 | ~1 in 3410 |
| Admixed American | 0.0050% | 3 / 60,020 | 0 | ~1 in 10000 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,608 | 0 | — |
| South Asian | 0.0033% | 3 / 91,076 | 0 | ~1 in 15180 |
| Finnish · under-sampled | 0.0016% | 1 / 62,506 | 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 457 in connecting loop. Neighbors: ALA458 (2.5 Å), ARG456 (2.5 Å — adjacent existing arginine!), TYR454 (3.7 Å), PRO453 (4.1 Å).
Replacing R457 with serine eliminates one of two adjacent arginines (R456 + R457). The local positively-charged surface character is reduced. ΔΔG 0.82 + AM 0.515 borderline + monogenic diabetes confirm severe consequence.
Druggability Assessment
Mechanism: loss of R457 charge from R456-R457 cluster. Therapeutic: site-directed at the loop's charged surface.
Why this matters
Feed this card to Wolfram Intelligence
Download the R457S 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.