YWHAZ

Chr 8AD

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

Also known as: 14-3-3-zeta, HEL-S-3, HEL-S-93, HEL4, KCIP-1, POPCHAS, YWHAD

NCBI Gene: 7534ENSG00000164924UniProt: P63104

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 sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. Several transcript variants that differ in the 5' UTR but that encode the same protein have been identified for this gene. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Popov-Chang syndromeMIM #618428
AD
95
ClinVar variants
45
Pathogenic / LP
0.94
pLI score· haploinsufficient
0
Active trials
Clinical Summary— YWHAZ
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 21 VUS of 95 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.36LOEUF
pLI 0.940
Z-score 3.13
OE 0.08 (0.03–0.36)
Highly constrained

More LoF-intolerant than ~75% 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.
3.10Z-score
OE missense 0.23 (0.17–0.32)
30 obs / 128.9 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.08 (0.03–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.23 (0.17–0.32)
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.0.97
0≤1.21.6
LoF obs/exp: 1 / 13.3Missense obs/exp: 30 / 128.9Syn Z: 0.17

ClinVar Variant Classifications

95 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic2
VUS21
Likely Benign19
Benign9
Conflicting1
43
Pathogenic
2
Likely Pathogenic
21
VUS
19
Likely Benign
9
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
3
39
0
43
Likely Pathogenic
0
0
2
0
2
VUS
1
8
12
0
21
Likely Benign
0
0
9
10
19
Benign
0
1
4
4
9
Conflicting
—1
Total212661495

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

View in ClinVar →

Protein Context — Lollipop Plot

YWHAZ · protein map & ClinVar variants

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

Gene2Phenotype Curations

YWHAZ-related developmental delay with simplified gyral pattern

limited
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Popov-Chang syndrome

MIM #618428

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications.
Scorrano G et al.·Genes (Basel)
2023Review
Identification and validation of extracellular vesicle reference genes for the normalization of RT-qPCR data.
Pinheiro C et al.·J Extracell Vesicles
2024
Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis.
Gao X et al.·J Biomed Sci
2025
A novel glycolysis-related gene signature for predicting prognosis and immunotherapy efficacy in breast cancer.
Huang R et al.·Front Immunol
2025
Heat Shock Strengthens the Protective Potential of MSCs in Liver Injury by Promoting EV Release Through Upregulated Autophagosome Formation.
Wang T et al.·J Extracell Vesicles
2025
YWHAZ variation causes intellectual disability and global developmental delay with brain malformation.
Wan RP et al.·Hum Mol Genet
2023
The clinical and prognostic significance of YWHAZ in non-small-cell lung cancer patients: Immunohistochemical analysis.
Deng Y et al.·J Cell Biochem
2019Cohort
Matrix stiffness regulates the protein profile of extracellular vesicles of pancreatic cancer cell lines.
Ferrara B et al.·Proteomics
2024
Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish.
Antón-Galindo E et al.·Mol Psychiatry
2022Functional
Cerebrospinal fluid proteome profiling across the Alzheimer's disease continuum: a step towards solving the equation for 'X'.
Weiner S et al.·Mol Neurodegener
2025
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