YWHAH

Chr 22

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

Also known as: YWHA1

NCBI Gene: 7533ENSG00000128245UniProt: Q04917OMIM: 113508

The YWHAH protein is a 14-3-3 adapter protein that regulates signaling pathways by binding to phosphoserine-containing proteins and modulating their activity. Mutations cause developmental and epileptic encephalopathy with early-onset seizures and intellectual disability, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants (LOEUF 0.504), reflecting its critical role in neurodevelopment.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 0.50
Clinical Summary— YWHAH
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
18 unique Pathogenic / Likely Pathogenic· 18 VUS of 43 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.50LOEUF
pLI 0.784
Z-score 2.54
OE 0.11 (0.04–0.50)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.56Z-score
OE missense 0.36 (0.28–0.46)
45 obs / 125.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.11 (0.04–0.50)
0≤0.351.4
Missense OE0.36 (0.28–0.46)
0≤0.61.4
Synonymous OE1.19
0≤1.21.6
LoF obs/exp: 1 / 9.4Missense obs/exp: 45 / 125.9Syn Z: -1.09
DN
0.7033th %ile
GOF
0.4677th %ile
LOF
0.3745th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

ClinVar Variant Classifications

43 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic1
VUS18
17
Pathogenic
1
Likely Pathogenic
18
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
17
0
17
Likely Pathogenic
0
0
1
0
1
VUS
0
15
3
0
18
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total01521036

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

View in ClinVar →

Protein Context — Lollipop Plot

YWHAH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients