ZNF483

Chr 9

zinc finger protein 483

The protein functions as a DNA-binding transcription factor that regulates gene transcription by RNA polymerase II in the nucleus. Mutations in ZNF483 are predicted to cause disease through a gain-of-function mechanism, though specific associated neurological conditions have not yet been definitively characterized. The gene shows extremely high intolerance to loss-of-function variants (pLI 0.97, LOEUF 0.32), indicating that haploinsufficiency is likely pathogenic and suggesting an autosomal dominant inheritance pattern.

ResearchSummary from RefSeq, UniProt, Mechanism

MultiplemechanismLOEUF 0.32

Clinical Summary— ZNF483

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). 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

0.32LOEUF

pLI 0.967

Z-score 4.23

OE 0.14 (0.07–0.32)

Highly constrained

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

Missense Constraint

2.40Z-score

OE missense 0.66 (0.59–0.73)

253 obs / 385.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.14 (0.07–0.32)

0≤0.351.4

Missense OE0.66 (0.59–0.73)

0≤0.61.4

Synonymous OE0.94

0≤1.21.6

LoF obs/exp: 4 / 28.3Missense obs/exp: 253 / 385.3Syn Z: 0.53

0.74top 25%

GOF

0.74top 25%

LOF

0.4528th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.32

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.