YWHAZ

protein-coding

tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta, the group of 14-3-3 phospho-serine/phospho-threonine binding proteins

Gene summary

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]

Previous symbols:

YWHAD

MANE transcript

NM_145690.3

Inheritance

ClinVar variants

P:9U:21B:14

Top phenotype

Popov-Chang syndrome

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr8:100,916,523-100,953,388

External References & Databases

Ensembl (ENSG00000164924)

Transcript & Mutation Effects

hg38 • Region Span ~36.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The *YWHAZ* gene is located on chromosome 8 at 8q22.3 and encodes the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta protein, which mediates signal transduction by binding to phosphoserine-containing proteins. *YWHAZ* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (Popov et al., PMID:31024343). Seven variants (missense, nonsense, and frameshift) that have been reported in 7 probands in 3 publications are included in this curation (PMIDs: 31024343, 23999528, 36001342, 35143101). This gene-disease relationship is also supported by experimental evidence including animal models that suggest that this gene contributes to neurobehavioral deficits, and plays a role in establishing neuronal connectivity and modulating neurotransmission (PMIDs: 35501409, 22124272, 26207352). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date August 15, 2025 (SOP Version 11).

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Illumina

Clinical Genomic Database (CGD)

Popov-Chang syndromeAD

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31024343

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to YWHAZ variants in ClinVar

9 Conditions Cataloged

not providedTotal: 43

not specifiedTotal: 10

Popov-Chang syndromeTotal: 9

YWHAZ-related developmental delay with simplified gyral patternTotal: 1

Cardiofaciocutaneous spectrum disorderTotal: 1

YWHAZ-related neurodevelopmental syndromeTotal: 1

Noonan-like disorderTotal: 1

YWHAZ-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145690.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	10 clinvar	3 clinvar	14
missense	3 clinvar	3 clinvar	10 clinvar		1 clinvar	17
nonsense	1 clinvar		2 clinvar			3
start loss			1 clinvar			1
frameshift	1 clinvar	1 clinvar	3 clinvar			5
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	5	4	21	10	4	44

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145690.3	RefSeq	NP_663723.1	5	MANE Select
ENST00000395958.6	Ensembl	ENSP00000379288.2	5	MANE Select
NM_001135699.2	RefSeq	NP_001129171.1	5	Standard
NM_001135700.2	RefSeq	NP_001129172.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Cell cycle - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)
Pathogenic Escherichia coli infection - Homo sapiens (human)

Biological Process

protein targeting
signal transduction
synaptic target recognition
cytokine-mediated signaling pathway
platelet activation

Molecular Function

RNA binding
protein binding
transcription factor binding
protein kinase binding
protein domain specific binding

Cellular Component

extracellular space
nucleus
nucleoplasm
cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395957
Coding exons: 5
Length: 36864
Individuals with no LoFs: 124788
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124789
p: 0.00000401

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.10	30	129	0.233	0.00000649	1594
Missense (PolyPhen)		2	41.16	0.048591		610
Synonymous	0.168	48	49.5	0.970	0.00000276	437
Loss of Function	3.13	1	13.3	0.0752	6.46e-7	169

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. {ECO:0000269|PubMed:14578935, ECO:0000269|PubMed:15071501, ECO:0000269|PubMed:15644438, ECO:0000269|PubMed:16376338, ECO:0000269|PubMed:9360956}.;

Recessive Scores

pRec: 0.586

Intolerance Scores

LoFtool: 0.410
RVIS EVS: 0.08
RVIS percentile EVS: 59.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low