ZSCAN32

Chr 16

zinc finger and SCAN domain containing 32

Also known as: HCCS-5, ZNF434

NCBI Gene: 54925 ENSG00000140987 UniProt: Q9NX65

The ZSCAN32 protein functions as a transcriptional regulator that binds to identical proteins and is predicted to regulate RNA polymerase II transcription in the nucleus. Mutations in this gene cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, affecting neurological development in early childhood. The gene shows tolerance to loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

ResearchSummary from RefSeq, UniProt

Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.57

Clinical Summary— ZSCAN32

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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

88 VUS of 102 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?

1.57LOEUF

pLI 0.000

Z-score -0.13

OE 1.04 (0.70–1.57)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.24Z-score

OE missense 1.21 (1.11–1.33)

324 obs / 266.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.04 (0.70–1.57)

0≤0.351.4

Missense OE?1.21 (1.11–1.33)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 16 / 15.4Missense obs/exp: 324 / 266.8Syn Z: -1.58

This gene — mechanism propensity

0.7130th %ile

GOF

0.6540th %ile

LOF

0.3549th %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

102 submitted variants in ClinVar

ClinVar

Classification Summary

VUS88

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	88	88
Likely Benign	5	5
Benign	0	0
Total	93	93

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 50) ClinVar copy-number / structural variants overlap ZSCAN32 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →