ZNF594

Chr 17

zinc finger protein 594

NCBI Gene: 84622 ENSG00000180626 UniProt: Q96JF6

ZNF594 encodes a zinc finger transcription factor that binds DNA and regulates RNA polymerase II-mediated transcription in the nucleus. The gene shows very low constraint against loss-of-function variants (pLI 0.0009, LOEUF 1.78), and no definitive disease associations have been established with ZNF594 mutations in pediatric patients.

ResearchSummary from RefSeq, UniProt

Predicted to enable DNA binding activity and zinc ion binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.78

Clinical Summary— ZNF594

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

136 VUS of 151 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.78LOEUF

pLI 0.000

Z-score -0.02

OE 1.01 (0.55–1.78)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.50Z-score

OE missense 1.35 (1.26–1.45)

549 obs / 407.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.01 (0.55–1.78)

0≤0.351.4

Missense OE?1.35 (1.26–1.45)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 6 / 6.0Missense obs/exp: 549 / 407.0Syn Z: -1.72

This gene — mechanism propensity

0.7228th %ile

GOF

0.6932th %ile

LOF

0.4039th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

151 submitted variants in ClinVar

ClinVar

Classification Summary

VUS136

Likely Benign12

136

VUS

Likely 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	136	0	136
Likely Benign	10	2	12
Benign	0	0	0
Total	146	2	148

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap ZNF594 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →