E273A
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorialGlutamate → Alanine at position 273 in N-terminal cytoplasmic domain. ClinVar Conflicting with broad spectrum — Cataract 41, DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.22. pLDDT 29 — Category 5 IDR! Same position as E273K.
Interactive 3D Structure
Computational Predictions
- pLDDT 28.91 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 Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- 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
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 East Asian: AF 0.098% (44 of 44,886 alleles), 33.6x 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. |
|---|---|---|---|---|
| East Asian | 0.098% | 44 / 44,886 | 0 | ~1 in 510 |
| Remaining individuals | 0.0032% | 2 / 62,458 | 0 | ~1 in 15610 |
| European (non-Finnish) · under-sampled | 0.000085% | 1 / 1,180,026 | 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 273 same as E273K — DEEP IDR (pLDDT 29). DynaMut2 untrustworthy here.
E273A is the second substitution at 273 (with E273K). Both deep-IDR Category 5. AM 0.12 under-call; multi-phenotype confirms clinical pathogenicity.
Druggability Assessment
The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity.
Why this matters
Feed this card to Wolfram Intelligence
Download the E273A 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.