YWHAG

Chr 7AD

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

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

NCBI Gene: 7532 ENSG00000170027 UniProt: P61981 OMIM: 605356

The protein belongs to the 14-3-3 family and mediates signal transduction by binding to phosphoserine-containing proteins, with particular expression in muscle tissues and interactions with RAF1 and protein kinase C. Mutations cause developmental and epileptic encephalopathy 56 through an autosomal dominant inheritance pattern. The high pLI score (0.96) and low LOEUF score (0.29) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, 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 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]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.291 OMIM phenotype

Clinical Summary— YWHAG

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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.

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ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 88 VUS of 238 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — YWHAG

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.29)

0≤0.351.4

Missense OE?0.34 (0.27–0.43)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 0 / 10.3Missense obs/exp: 54 / 158.6Syn Z: -1.71

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongYWHAG-related early-onset epilepsyGOFAD

This gene — mechanism propensity

0.5082th %ile

GOF

0.4381th %ile

LOF

0.58top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 48% of P/LP variants are LoF · LOEUF 0.29

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.

Literature Evidence

LOFTwo unrelated human patients with interstitial deletions at chromosome 7q11.23 (613729) including the YWHAG gene had severe infantile seizures and hypertrophic cardiomyopathy, which Komoike et al. (2010) postulated may have resulted from haploinsufficiency of YWHAG.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 20146355 ↗

ClinVar Variant Classifications

238 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic12

VUS88

Likely Benign103

Benign7

Conflicting4

Pathogenic

Likely Pathogenic

VUS

103

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	7	1	0	21
Likely Pathogenic	3	8	1	0	12
VUS	8	75	5	0	88
Likely Benign	0	2	10	91	103
Benign	0	1	1	5	7
Conflicting	—				4
Total	24	93	18	96	235

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap YWHAG — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →