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: 7531 ENSG00000108953 UniProt: P62258 OMIM: 605066

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.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.23

Clinical Summary— YWHAE

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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.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 13 VUS of 89 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — YWHAE

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.23)

0≤0.351.4

Missense OE?0.34 (0.27–0.43)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 0 / 12.7Missense obs/exp: 49 / 145.0Syn Z: -0.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateYWHAE-related developmental delay, seizures, hypotonia and brain abnormalitiesOTHERAD

This gene — mechanism propensity

0.6648th %ile

GOF

0.3887th %ile

LOF

0.4627th %ile

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.

LOFLOEUF 0.23

DNprediction above median

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

89 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS13

Likely Benign30

Benign23

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	1	0	0	0	1
VUS	0	11	2	0	13
Likely Benign	0	0	18	12	30
Benign	0	0	22	1	23
Total	1	11	43	13	68

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

124 pathogenic / likely-pathogenic (of 162) ClinVar copy-number / structural variants overlap YWHAE — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →