GATA3

Chr 10AD

GATA binding protein 3

Also known as: HDR, HDRS

NCBI Gene: 2625 ENSG00000107485 UniProt: P23771

The GATA3 transcription factor binds to specific DNA sequences to regulate T-cell development and differentiation, particularly in Th2 immune responses, and also functions in endothelial cell biology. Loss-of-function mutations cause autosomal dominant hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR syndrome). The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the underlying disease mechanism.

Summary from RefSeq, OMIM, UniProt, Mechanism

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Primary Disease Associations & Inheritance

Hypoparathyroidism, sensorineural deafness, and renal dysplasiaMIM #146255

Active trials

525

Pubs (1 yr)

162

P/LP submissions

13%

P/LP missense

0.39

LOEUF

LOF

Mechanism· G2P

Clinical Summary— GATA3

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Gene-Disease Validity (ClinGen)

hypoparathyroidism-deafness-renal disease syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.90) — some intolerance to loss-of-function variants.

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ClinVar Variants

119 unique Pathogenic / Likely Pathogenic· 176 VUS of 460 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — GATA3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.39LOEUF

pLI 0.899

Z-score 3.27

OE 0.12 (0.05–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

1.91Z-score

OE missense 0.67 (0.59–0.76)

181 obs / 269.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.12 (0.05–0.39)

0≤0.351.4

Missense OE0.67 (0.59–0.76)

0≤0.61.4

Synonymous OE1.33

0≤1.21.6

LoF obs/exp: 2 / 16.2Missense obs/exp: 181 / 269.3Syn Z: -2.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGATA3-related hypoparathyroidism, sensorineural deafness, and renal diseaseLOFAD

0.4686th %ile

GOF

0.2398th %ile

LOF

0.89top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.39

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNNovel dominant-negative mutant of GATA3 in HDR syndrome.PMID:21120445

GOFIn this study, we identify differential functional consequences of mutation types in GATA3. We present evidence that the most common mutation type results in a protein with elongated C-terminus that displays effects consistent with gain-of-function activity in a cell line model.PMID:27588951

LOFGATA3 haplo-insufficiency causes human HDR syndromePMID:10935639

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