A243V
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialAlanine → Valine at position 243 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes. AlphaMissense 0.27 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.93.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | D246 | D246 | Preserved |
| Hydrogen bond | F247 | F247 | Preserved |
| Polar contact | D245 | — | Lost |
| Polar contact | D246 | D246 | Preserved |
| Polar contact | F247 | F247 | Preserved |
| Van der Waals | D245 | — | Lost |
| Van der Waals | — | F247 | Gained |
| Hydrophobic | Q194 | Q194 | Preserved |
| Hydrophobic | — | D246 | 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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant); Ataxia / spastic ataxia (inheritance not specified); 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); 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 diabetesautosomal dominantsubmitted as: Monogenic diabetes; Type 2 diabetes mellitus
- Ataxia / spastic ataxiainheritance not specifiedsubmitted as: Hereditary ataxia
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- 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
- 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 South Asian: AF 0.108% (98 of 91,090 alleles), 2.7x the global figure. The global AF describes the general population, not the at-risk group.
1 homozygote reported in gnomAD v4 (1 South Asian). 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. |
|---|---|---|---|---|
| South Asian | 0.108% | 98 / 91,090 | 1 | ~1 in 460 |
| Remaining individuals | 0.056% | 35 / 62,498 | 0 | ~1 in 890 |
| European (non-Finnish) | 0.043% | 503 / 1,180,020 | 0 | ~1 in 1170 |
| Admixed American | 0.0067% | 4 / 60,026 | 0 | ~1 in 7500 |
| African / African American | 0.0067% | 5 / 75,054 | 0 | ~1 in 7510 |
| Finnish | 0.0047% | 3 / 63,456 | 0 | ~1 in 10580 |
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 243 in cytoplasmic domain. Neighbors: LEU244 (2.5 Å), ILE242 (2.5 Å), LYS193 (4.0 Å — long-range contact!). The K193 long-range contact suggests A243 sits in a structural element bringing distant sequence positions into contact.
|ΔΔG| 0.93 substantial for conservative substitution. AM 0.27 under-call; monogenic diabetes does not resolve it (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: volume mismatch perturbing K193 long-range contact. Therapeutic: site-directed at the 193-243 cross-fold geometry.
Why this matters
Feed this card to Wolfram Intelligence
Download the A243V 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.