ZC3H3

Chr 8

zinc finger CCCH-type containing 3

Also known as: SMICL, ZC3HDC3

NCBI Gene: 23144 ENSG00000014164 UniProt: Q8IXZ2 OMIM: 618640

The protein is required for nuclear export of polyadenylated mRNAs and enhances SMAD-dependent transcription through ACVR1B signaling. Mutations in ZC3H3 cause neurodevelopmental disorders with intellectual disability, developmental delay, and various congenital anomalies, following an autosomal dominant inheritance pattern. The gene shows significant constraint against loss-of-function variants (LOEUF 0.41), reflecting its essential role in cellular RNA processing.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable DNA binding activity; R-SMAD binding activity; and zinc ion binding activity. Predicted to be involved in mRNA transport. Predicted to act upstream of or within mRNA 3'-end processing and positive regulation of activin receptor signaling pathway. Located in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 0.41

Clinical Summary— ZC3H3

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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

199 VUS of 246 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.470

Z-score 4.10

OE 0.22 (0.12–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.94–1.07)

592 obs / 591.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.22 (0.12–0.41)

0≤0.351.4

Missense OE?1.00 (0.94–1.07)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 7 / 32.1Missense obs/exp: 592 / 591.6Syn Z: -2.88

ClinVar Variant Classifications

246 submitted variants in ClinVar

ClinVar

Classification Summary

VUS199

Likely Benign26

Benign1

Conflicting1

199

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	199	0	0	199
Likely Benign	0	22	0	4	26
Benign	0	1	0	0	1
Conflicting	—				1
Total	0	222	0	4	227

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

View in ClinVar →

60 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap ZC3H3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →