YWHAH

Chr 22

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

Also known as: YWHA1

NCBI Gene: 7533 ENSG00000128245 UniProt: Q04917 OMIM: 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.

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 99% identical to the mouse, rat and bovine orthologs. This gene contains a 7 bp repeat sequence in its 5' UTR, and changes in the number of this repeat have been associated with early-onset schizophrenia and psychotic bipolar disorder. [provided by RefSeq, Jun 2009]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.50

Clinical Summary— YWHAH

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

15 VUS of 22 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 OE?0.11 (0.04–0.50)

0≤0.351.4

Missense OE?0.36 (0.28–0.46)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 1 / 9.4Missense obs/exp: 45 / 125.9Syn Z: -1.09

This gene — mechanism propensity

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

22 submitted variants in ClinVar

ClinVar

Classification Summary

VUS15

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	15	15
Likely Benign	0	0
Benign	0	0
Total	15	15

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap YWHAH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →