ZFHX3

Chr 16ADAR

zinc finger homeobox 3

Also known as: ATBF1, ATBT, ATFB8, C16orf47, EIG20, SCA4, ZFH-3, ZNF927

NCBI Gene: 463ENSG00000140836UniProt: Q15911

This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. Multiple transcript variants expressed from alternate promoters and encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

Primary Disease Associations & Inheritance

{Atrial fibrillation 8, susceptibility to}MIM #613055
AD
Epilepsy, idiopathic generalized 20MIM #621500
AR
Prostate cancer, somaticMIM #176807
Spinocerebellar ataxia 4MIM #600223
AD
658
ClinVar variants
35
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ZFHX3
⚡
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.
📋
ClinVar Variants
35 Pathogenic / Likely Pathogenic· 524 VUS of 658 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.14LOEUF
pLI 1.000
Z-score 9.52
OE 0.08 (0.05–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
-1.23Z-score
OE missense 1.08 (1.04–1.11)
2279 obs / 2119.1 exp
Tolerant

Tolerant to missense variation

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 (0.05–0.14)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (1.04–1.11)
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.1.26
0≤1.21.6
LoF obs/exp: 10 / 124.8Missense obs/exp: 2279 / 2119.1Syn Z: -6.30

ClinVar Variant Classifications

658 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic13
VUS524
Likely Benign78
Benign16
Conflicting5
22
Pathogenic
13
Likely Pathogenic
524
VUS
78
Likely Benign
16
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
2
15
0
22
Likely Pathogenic
7
1
5
0
13
VUS
19
484
18
3
524
Likely Benign
0
17
12
49
78
Benign
0
5
6
5
16
Conflicting
—5
Total315095657658

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

View in ClinVar →

Protein Context — Lollipop Plot

ZFHX3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ZFHX3-related neurodevelopmental disorder

moderate
ADLoss Of FunctionDecreased Gene Product Level
Dev. Disorders
G2P ↗
stop gained NMD triggeringframeshift variant NMD triggering

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Atrial fibrillation 8, susceptibility to}

MIM #613055

Molecular basis of disorder known

Autosomal dominant

Epilepsy, idiopathic generalized 20

MIM #621500

Molecular basis of disorder known

Autosomal recessive

Prostate cancer, somatic

MIM #176807

Molecular basis of disorder known

Spinocerebellar ataxia 4

MIM #600223

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ZFHX3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies.
Liu Q et al.·Cell
2024
An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.
Rudaks LI et al.·Cerebellum
2024Review
Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions.
Pellerin D et al.·Curr Neurol Neurosci Rep
2025Review
Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs.
Paucar M et al.·J Intern Med
2024
Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients.
Saffie-Awad P et al.·Mov Disord
2025Cohort
ZFHX3-associated neural tube defect.
Dutta D et al.·BMJ Case Rep
2025Case report
A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.
Figueroa KP et al.·Nat Genet
2024
Patterns of CTCF and ZFHX3 Mutation and Associated Outcomes in Endometrial Cancer.
Walker CJ et al.·J Natl Cancer Inst
2015
Rs7193343 polymorphism in zinc finger homeobox 3 (ZFHX3) gene and atrial fibrillation: an updated meta-analysis of 10 case-control comparisons.
Zhai C et al.·BMC Cardiovasc Disord
2015Meta-analysis
Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation.
van Ouwerkerk AF et al.·Circ Res
2020Review
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