ZC3H18

Chr 16

zinc finger CCCH-type containing 18

Also known as: NHN1

NCBI Gene: 124245 ENSG00000158545 UniProt: Q86VM9 OMIM: 620956

The protein enables mRNA cap binding and functions as a protein-macromolecule adaptor involved in RNA destabilization within nuclear speckles as part of ribonucleoprotein complexes. Mutations cause autosomal recessive neurodevelopmental disorder with macrocephaly, seizures, and developmental delay. This gene is highly constrained against loss-of-function variation (pLI ~1.0, LOEUF 0.126), indicating that complete loss of function is likely incompatible with survival.

OMIM ResearchSummary from RefSeq

Enables mRNA cap binding complex binding activity and protein-macromolecule adaptor activity. Involved in RNA destabilization. Located in nuclear speck. Part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— ZC3H18

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

146 VUS of 181 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 6.30

OE 0.04 (0.01–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

0.58Z-score

OE missense 0.93 (0.87–1.00)

580 obs / 620.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.13)

0≤0.351.4

Missense OE?0.93 (0.87–1.00)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 2 / 50.1Missense obs/exp: 580 / 620.7Syn Z: -2.96

This gene — mechanism propensity

0.19100th %ile

GOF

0.2298th %ile

LOF

0.88top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.13

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

181 submitted variants in ClinVar

ClinVar

Classification Summary

VUS146

Likely Benign10

Benign1

146

VUS

Likely Benign

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	146	0	146
Likely Benign	7	3	10
Benign	0	1	1
Total	153	4	157

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

View in ClinVar →

62 pathogenic / likely-pathogenic (of 86) ClinVar copy-number / structural variants overlap ZC3H18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →