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 RNA catabolic process. 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, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.41

LOEUF

—

Mechanism

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

Background carrier burden — how many people carry a rare variant somewhere in ZC3H3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 27

1,455 rare PASS variants

Rare truncating (LoF)

1 in 920

133 rare PASS variants

Rare synonymous (reference)

1 in 50

693 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZC3H3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 37	1 in 1,000
South Asian	~43k	1 in 26	1 in 850
Remaining (unassigned)	~30k	1 in 26	1 in 2,200
European (Finnish)	~27k	1 in 96	1 in 1,900
Admixed American	~22k	1 in 25	1 in 740
African / African American	~21k	1 in 22	1 in 500
East Asian	~20k	1 in 31	1 in 1,000
Ashkenazi Jewish	~13k	1 in 110	none seen
Middle Eastern	~2,884	1 in 30	≈ 1 in 1,100

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 12 coding exons well covered in gnomAD exomes; exon 10 marginal. Genomes: all 12.? see exons ↓