ZNF768

Chr 16

zinc finger protein 768

NCBI Gene: 79724 ENSG00000169957 UniProt: Q9H5H4 OMIM: 618032

ZNF768 encodes a transcription factor that binds to specific DNA sequences called mammalian-wide interspersed repeats (MIRs) in gene promoter regions and is required for cellular homeostasis. Mutations cause autosomal recessive neurodevelopmental disorder with microcephaly, epilepsy, and brain malformations. The gene is highly constrained against loss-of-function variants (LOEUF 0.498), consistent with the severe developmental phenotypes observed when both copies are disrupted.

OMIM 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 be located in chromosome. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.50

Clinical Summary— ZNF768

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

68 VUS of 75 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.424

Z-score 3.11

OE 0.22 (0.11–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.72Z-score

OE missense 0.59 (0.53–0.67)

212 obs / 356.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.11–0.50)

0≤0.351.4

Missense OE?0.59 (0.53–0.67)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 18.4Missense obs/exp: 212 / 356.4Syn Z: -1.15

This gene — mechanism propensity

0.6744th %ile

GOF

0.6052th %ile

LOF

0.55top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

75 submitted variants in ClinVar

ClinVar

Classification Summary

VUS68

Likely Benign5

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	68	0	68
Likely Benign	4	1	5
Benign	0	0	0
Total	72	1	73

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap ZNF768 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →