GATA6

Chr 18AD

GATA binding protein 6

This zinc finger transcription factor regulates cellular differentiation and organogenesis during embryonic development, particularly in gut, lung, and heart tissues. Mutations cause autosomal dominant congenital heart defects including atrial septal defects, atrioventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus, as well as pancreatic agenesis with congenital heart defects. The gene is highly constrained against loss-of-function variants (pLI 0.997), reflecting its critical role in early development.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

Atrial septal defect 9MIM #614475
AD
Atrioventricular septal defect 5MIM #614474
AD
Pancreatic agenesis and congenital heart defectsMIM #600001
AD
Persistent truncus arteriosusMIM #217095
Tetralogy of FallotMIM #187500
AD
UniProtConotruncal heart malformations
0
Active trials
113
Pubs (1 yr)
2
P/LP submissions
P/LP missense
0.17
LOEUF· LoF intol.
LOF
Mechanism· G2P
Clinical SummaryGATA6
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Gene-Disease Validity (ClinGen)
GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
2 unique Pathogenic / Likely Pathogenic· 56 VUS of 100 total submissions
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GeneReview available — GATA6
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.17LOEUF
pLI 0.997
Z-score 3.84
OE 0.00 (0.000.17)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.28Z-score
OE missense 0.79 (0.700.88)
222 obs / 282.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.00 (0.000.17)
00.351.4
Missense OE0.79 (0.700.88)
00.61.4
Synonymous OE1.02
01.21.6
LoF obs/exp: 0 / 17.2Missense obs/exp: 222 / 282.7Syn Z: -0.17
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveGATA6-related atrial septal defectOTHERAD
definitiveGATA6-related pancreatic agenesis, diaphragmatic hernia, and congenital heart defectsLOFAD
definitiveGATA6-related atrioventricular septal defectOTHERAD
DN
0.2798th %ile
GOF
0.2696th %ile
LOF
0.93top 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 · LOEUF 0.17
DN1 literature citation
GOF1 literature citation

Literature Evidence

DNMoreover, the E486del mutant possessed dominant negative activity on the SEMA3C and PLXNA2 promoter when mixed with wild-type GATA6, whereas the N466H mutant exhibited no significant interaction with wild-type GATA6PMID:19666519
GOFGain-of-function mutations in GATA6 lead to atrial fibrillation.PMID:27756709
LOFGenome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development.PMID:28196600

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

ClinVar Variant Classifications

100 submitted variants in ClinVar

Classification Summary

Pathogenic2
VUS56
Likely Benign41
Conflicting1
2
Pathogenic
56
VUS
41
Likely Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
1
0
2
Likely Pathogenic
0
0
0
0
0
VUS
0
50
6
0
56
Likely Benign
0
1
9
31
41
Benign
0
0
0
0
0
Conflicting
1
Total1511631100

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

View in ClinVar →

Protein Context — Lollipop Plot

GATA6 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗