ZBTB4

Chr 17

zinc finger and BTB domain containing 4

Also known as: KAISO-L1, ZNF903

NCBI Gene: 57659 ENSG00000174282 UniProt: Q9P1Z0

This gene encodes a transcriptional repressor that binds to methylated CpG dinucleotides and regulates gene expression in a DNA methylation-dependent manner, with additional roles in DNA damage response and postnatal muscle development. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.11), but no associated human diseases have been established to date. Given the high constraint scores, pathogenic variants in ZBTB4 would be expected to cause developmental disorders, but clinical phenotypes remain to be defined.

ResearchSummary from RefSeq, UniProt

Enables several functions, including DNA-binding transcription repressor activity, RNA polymerase II-specific; nucleotide binding activity; and protein homodimerization activity. Involved in DNA damage response and negative regulation of transcription by RNA polymerase II. Located in cytosol and nuclear body. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.11

Clinical Summary— ZBTB4

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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

199 VUS of 233 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 4.76

OE 0.00 (0.00–0.11)

Highly constrained

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

Missense Constraint?

1.93Z-score

OE missense 0.78 (0.73–0.84)

498 obs / 634.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.11)

0≤0.351.4

Missense OE?0.78 (0.73–0.84)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 0 / 26.3Missense obs/exp: 498 / 634.9Syn Z: -0.34

This gene — mechanism propensity

0.2099th %ile

GOF

0.3292th %ile

LOF

0.88top 5%

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

LOFprediction above median · LOEUF 0.11

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

233 submitted variants in ClinVar

ClinVar

Classification Summary

VUS199

Likely Benign21

Benign8

199

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	199	0	199
Likely Benign	18	3	21
Benign	3	5	8
Total	220	8	228

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap ZBTB4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →