YWHAG

Chr 7

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

Also known as: 14-3-3GAMMA, DEE56, EIEE56, PPP1R170

NCBI Gene: 7532ENSG00000170027UniProt: P61981

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 rat ortholog. It is induced by growth factors in human vascular smooth muscle cells, and is also highly expressed in skeletal and heart muscles, suggesting an important role for this protein in muscle tissue. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 56
273
ClinVar variants
58
Pathogenic / LP
0.96
pLI score· haploinsufficient
0
Active trials
Clinical Summary— YWHAG
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 100 VUS of 273 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.29LOEUF
pLI 0.964
Z-score 2.98
OE 0.00 (0.00–0.29)
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.
2.95Z-score
OE missense 0.34 (0.27–0.43)
54 obs / 158.6 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 (0.00–0.29)
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.1.26
0≤1.21.6
LoF obs/exp: 0 / 10.3Missense obs/exp: 54 / 158.6Syn Z: -1.71

ClinVar Variant Classifications

273 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic15
VUS100
Likely Benign103
Benign8
Conflicting4
43
Pathogenic
15
Likely Pathogenic
100
VUS
103
Likely Benign
8
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
7
30
0
43
Likely Pathogenic
1
6
8
0
15
VUS
4
70
26
0
100
Likely Benign
0
2
10
91
103
Benign
0
1
2
5
8
Conflicting
—4
Total11867696273

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

View in ClinVar →

Protein Context — Lollipop Plot

YWHAG · protein map & ClinVar variants

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

Gene2Phenotype Curations

YWHAG-related early-onset epilepsy

strong
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease.
Guo Y et al.·Nat Hum Behav
2024
Clinical and molecular characterization of patients with YWHAG-related epilepsy.
Cetica V et al.·Epilepsia
2024Cohort
YWHAG promotes bladder cancer metastasis by regulating TMOD3 to activate ERK1/2 and JNK phosphorylation in the MAPK pathway.
Tian T et al.·J Transl Med
2024
Epilepsy and electroencephalogram evolution in YWHAG gene mutation: A new phenotype and review of the literature.
Stern T et al.·Am J Med Genet A
2021Review
Exploring the role of m6A methylation regulators in glioblastoma multiforme and their impact on the tumor immune microenvironment.
Deng X et al.·FASEB J
2023
A heterozygous missense variant in the YWHAG gene causing developmental and epileptic encephalopathy 56 in a Chinese family.
Yi Z et al.·BMC Med Genomics
2022
YWHAG Deficiency Disrupts the EMT-Associated Network to Induce Oxidative Cell Death and Prevent Metastasis.
Lee JXT et al.·Adv Sci (Weinh)
2023
Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature.
Amato ME et al.·Eur J Paediatr Neurol
2024Review
Unraveling molecular characteristics and functional exploration of panoptosis for prognosis stratification in lung adenocarcinoma: a tumor marker prognostic study.
Hu K et al.·Int J Surg
2025Functional
Serum level of YWHAG as a diagnostic marker of cognitive impairment in Parkinson's disease patients.
Peng Y et al.·Acta Neurol Belg
2024Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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