ZZEF1

Chr 17

zinc finger ZZ-type and EF-hand domain containing 1

Also known as: ZZZ4

NCBI Gene: 23140 ENSG00000074755 UniProt: O43149

The ZZEF1 protein functions as a histone H3 reader that acts as a transcriptional coactivator for KLF6 and KLF9 transcription factors, with predicted roles in glutamatergic synaptic transmission and visual learning. Mutations cause autosomal dominant developmental delay with seizures and dysmorphic features, typically presenting in early childhood. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

ResearchSummary from RefSeq, UniProt

Enables histone reader activity; lysine-acetylated histone binding activity; and methylated histone binding activity. Predicted to act upstream of or within several processes, including glutamatergic synaptic transmission; regulation of peptidyl-tyrosine phosphorylation; and visual learning. Predicted to be located in cell surface; postsynapse; and presynaptic active zone. [provided by Alliance of Genome Resources, Apr 2025]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.29

Clinical Summary— ZZEF1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.

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ClinVar Variants

427 VUS of 512 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.29LOEUF

pLI 0.835

Z-score 8.92

OE 0.22 (0.16–0.29)

Highly constrained

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

Missense Constraint?

1.05Z-score

OE missense 0.93 (0.89–0.97)

1534 obs / 1653.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.16–0.29)

0≤0.351.4

Missense OE?0.93 (0.89–0.97)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 33 / 151.4Missense obs/exp: 1534 / 1653.8Syn Z: -1.29

This gene — mechanism propensity

0.3892th %ile

GOF

0.4184th %ile

LOF

0.67top 25%

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

LOFprediction above median · LOEUF 0.29

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

512 submitted variants in ClinVar

ClinVar

Classification Summary

VUS427

Likely Benign28

Benign1

Conflicting1

427

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	427	0	0	427
Likely Benign	1	21	0	6	28
Benign	0	1	0	0	1
Conflicting	—				1
Total	1	449	0	6	457

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 52) ClinVar copy-number / structural variants overlap ZZEF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →