YWHAE
Chr 17tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon
Also known as: 14-3-3E, HEL2, KCIP-1, MDCR, MDS
The protein mediates signal transduction by binding to phosphoserine-containing proteins and interacts with key regulators of cell division and insulin sensitivity including CDC25 phosphatases, RAF1, and IRS1. Heterozygous mutations cause autosomal dominant developmental and epileptic encephalopathy with intellectual disability, seizures, and developmental delay. The high pLI score (0.98) and low LOEUF score (0.24) indicate the pathogenic mechanism involves haploinsufficiency, where loss of one functional copy is sufficient to cause disease.
Some data sources returned errors (1)
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Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Moderately missense-constrained (top ~2.5%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
250 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 97 | 0 | 97 |
Likely Pathogenic | 1 | 0 | 27 | 0 | 28 |
VUS | 0 | 11 | 34 | 0 | 45 |
Likely Benign | 0 | 0 | 23 | 12 | 35 |
Benign | 0 | 0 | 22 | 1 | 23 |
| Total | 1 | 11 | 203 | 13 | 228 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
YWHAE · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools