ZNF684

Chr 1

zinc finger protein 684

NCBI Gene: 127396 ENSG00000117010 UniProt: Q5T5D7

The protein is a transcriptional regulator that binds to specific DNA sequences and is predicted to be involved in innate immune responses and antiviral activity. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in early infancy. The gene shows moderate constraint against loss-of-function variants.

ResearchSummary from RefSeq, UniProt

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within innate immune response and negative regulation of single stranded viral RNA replication via double stranded DNA intermediate. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.48

Clinical Summary— ZNF684

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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

46 VUS of 54 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?

1.48LOEUF

pLI 0.000

Z-score 0.27

OE 0.92 (0.59–1.48)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.65Z-score

OE missense 0.87 (0.77–0.99)

169 obs / 194.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.92 (0.59–1.48)

0≤0.351.4

Missense OE?0.87 (0.77–0.99)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 12 / 13.1Missense obs/exp: 169 / 194.6Syn Z: 1.27

This gene — mechanism propensity

0.75top 25%

GOF

0.7126th %ile

LOF

0.3843th %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

54 submitted variants in ClinVar

ClinVar

Classification Summary

VUS46

Likely Benign3

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	46	0	46
Likely Benign	2	1	3
Benign	0	0	0
Total	48	1	49

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap ZNF684 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →