ZNF74

Chr 22

zinc finger protein 74

Also known as: COS52, ZFP520, ZNF520, hZNF7

NCBI Gene: 7625 ENSG00000185252 UniProt: Q16587 OMIM: 194548

The ZNF74 protein functions as a DNA-binding transcription factor that regulates RNA polymerase II-mediated transcription and may be involved in RNA metabolism. This gene is highly constrained against loss-of-function variants (pLI ~1.0), suggesting that mutations would likely cause severe developmental effects, though no specific disease associations have been established in the clinical literature to date.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in actin cytoskeleton and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.89

Clinical Summary— ZNF74

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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

93 VUS of 106 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.89LOEUF

pLI 0.000

Z-score 1.96

OE 0.56 (0.36–0.89)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.14Z-score

OE missense 0.85 (0.78–0.92)

371 obs / 438.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.36–0.89)

0≤0.351.4

Missense OE?0.85 (0.78–0.92)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 13 / 23.2Missense obs/exp: 371 / 438.4Syn Z: 1.07

This gene — mechanism propensity

0.90top 5%

GOF

0.84top 5%

LOF

0.1895th %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

106 submitted variants in ClinVar

ClinVar

Classification Summary

VUS93

Likely Benign6

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	92	0	93
Likely Benign	0	5	1	6
Benign	0	0	0	0
Total	1	97	1	99

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

View in ClinVar →

355 pathogenic / likely-pathogenic (of 395) ClinVar copy-number / structural variants overlap ZNF74 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →