YWHAE

Chr 17

tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon

Also known as: 14-3-3E, HEL2, KCIP-1, MDCR, MDS

NCBI Gene: 7531ENSG00000108953UniProt: P62258

This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 100% identical to the mouse ortholog. It interacts with CDC25 phosphatases, RAF1 and IRS1 proteins, suggesting its role in diverse biochemical activities related to signal transduction, such as cell division and regulation of insulin sensitivity. It has also been implicated in the pathogenesis of small cell lung cancer. Two transcript variants, one protein-coding and the other non-protein-coding, have been found for this gene. [provided by RefSeq, Aug 2008]

227
ClinVar variants
124
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— YWHAE
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
124 Pathogenic / Likely Pathogenic· 45 VUS of 227 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.23LOEUF
pLI 0.985
Z-score 3.30
OE 0.00 (0.00–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.83Z-score
OE missense 0.34 (0.27–0.43)
49 obs / 145.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.34 (0.27–0.43)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 0 / 12.7Missense obs/exp: 49 / 145.0Syn Z: -0.42

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic96
Likely Pathogenic28
VUS45
Likely Benign35
Benign23
96
Pathogenic
28
Likely Pathogenic
45
VUS
35
Likely Benign
23
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
96
0
96
Likely Pathogenic
0
0
28
0
28
VUS
0
10
35
0
45
Likely Benign
0
0
23
12
35
Benign
0
0
22
1
23
Total01020413227

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.

Gene2Phenotype Curations

YWHAE-related developmental delay, seizures, hypotonia and brain abnormalities

moderate
ADUndeterminedAbsent Gene Product
Dev. Disorders
G2P ↗
splice region variantframeshift variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
📖
GeneReview available — YWHAE
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.
Curry CJ et al.·Am J Med Genet A
2013Case report
Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome.
Baker EK et al.·Am J Med Genet A
2023Review
KDM2B-Rearranged Soft Tissue Sarcomas Expand the Concept of BCOR-Associated Sarcoma.
Motoi T et al.·Mod Pathol
2023
Clinical characteristics and outcomes for children, adolescents and young adults with "CIC-fused" or "BCOR-rearranged" soft tissue sarcomas: A multi-institutional European retrospective analysis.
Sparber-Sauer M et al.·Cancer Med
2023
Clinical findings and genetic analysis of patients with copy number variants involving 17p13.3 using a single nucleotide polymorphism array: a single-center experience.
Liang B et al.·BMC Med Genomics
2022Cohort
Endometrial Stromal Sarcomas With BCOR Internal Tandem Duplication and Variant BCOR/BCORL1 Rearrangements Resemble High-grade Endometrial Stromal Sarcomas With Recurrent CDK4 Pathway Alterations and MDM2 Amplifications.
Kommoss FKF et al.·Am J Surg Pathol
2022
The clinical phenotype of YWHAE-NUTM2B/E positive pediatric clear cell sarcoma of the kidney.
Gooskens SL et al.·Genes Chromosomes Cancer
2016
Deep clinical and genetic analysis of 17p13.3 region: 38 pediatric patients diagnosed using next-generation sequencing and literature review.
Ji X et al.·BMC Med Genomics
2025Review
AI-assisted multi-OMICS analysis reveals new markers for the prediction of AD.
Latifi-Navid H et al.·Biochim Biophys Acta Mol Basis Dis
2025
YWHAE promotes proliferation, metastasis, and chemoresistance in breast cancer cells.
Yang YF et al.·Kaohsiung J Med Sci
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
An adult patient with pulmonary atresia with ventricular septal defect and chromosome 17p13.3 microdeletion including YWHAE gene.
McDonnell E et al.·Cardiol Young
2026
[YWHAE-rearranged clear cell sarcoma of kidney: a clinicopathological analysis of seven cases].
Xing ZW et al.·Zhonghua Bing Li Xue Za Zhi
2026Cohort
Behavioral analyses of a forebrain glutamatergic neuron specific Ywhae conditional knockout mouse model.
Navarrete-Mathews M et al.·PLoS One
2025🔓 Open AccessFunctional
Congenital Undifferentiated Retroperitoneal Sarcoma With YWHAE::NUTM2B Fusion From the Abdomen to the Brain.
Torres Nunez MR et al.·J Pediatr Hematol Oncol
2025
Synergistic epigenetic modulation by 5-aza-2'-deoxycytidine and Wnt3a drives osteogenic trans-differentiation of 3T3-L1 pre-adipocytes through Ywhah and Ywhae.
Park SG et al.·Epigenomics
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools