ZNF654

Chr 3

zinc finger protein 654

NCBI Gene: 55279 ENSG00000175105 UniProt: Q8IZM8

ZNF654 encodes a transcription factor that binds DNA and regulates gene transcription by RNA polymerase II in the nucleus. Mutations cause autosomal dominant intellectual disability with seizures, and the gene is highly constrained against loss-of-function variants (pLI 0.997, LOEUF 0.17), indicating that even single functional copies are critical for normal development.

ResearchSummary from RefSeq, UniProt

Predicted to enable DNA binding activity and DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.17

Clinical Summary— ZNF654

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 0.998

Z-score 3.89

OE 0.00 (0.00–0.17)

Highly constrained

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

Missense Constraint?

1.13Z-score

OE missense 0.82 (0.73–0.91)

245 obs / 300.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.82 (0.73–0.91)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 0 / 17.6Missense obs/exp: 245 / 300.1Syn Z: 0.73

This gene — mechanism propensity

0.2598th %ile

GOF

0.3392th %ile

LOF

0.77top 5%

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

LOFprediction above median · LOEUF 0.17

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