ZFHX3

Chr 16ADAR

zinc finger homeobox 3

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

This gene encodes a transcription factor that regulates myogenic and neuronal differentiation and controls circadian locomotor rhythms in the brain. Mutations cause spinocerebellar ataxia 4, idiopathic generalized epilepsy, and susceptibility to atrial fibrillation with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.136), indicating intolerance to protein-truncating mutations.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAD/ARLOEUF 0.144 OMIM phenotypes
Clinical SummaryZFHX3
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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GeneReview available — ZFHX3
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.14LOEUF
pLI 1.000
Z-score 9.52
OE 0.08 (0.050.14)
Highly constrained

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

Missense Constraint
-1.23Z-score
OE missense 1.08 (1.041.11)
2279 obs / 2119.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.08 (0.050.14)
00.351.4
Missense OE1.08 (1.041.11)
00.61.4
Synonymous OE1.26
01.21.6
LoF obs/exp: 10 / 124.8Missense obs/exp: 2279 / 2119.1Syn Z: -6.30
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
moderateZFHX3-related neurodevelopmental disorderLOFAD
DN
0.2897th %ile
GOF
0.2597th %ile
LOF
0.85top 5%

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

LOFprediction above median · LOEUF 0.14

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

0 submitted variants 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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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