ZNRF3

Chr 22

zinc and ring finger 3

Also known as: BK747E2.3, RNF203

NCBI Gene: 84133ENSG00000183579UniProt: Q9ULT6

Enables frizzled binding activity and ubiquitin-protein transferase activity. Involved in negative regulation of Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

196
ClinVar variants
34
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ZNRF3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
34 Pathogenic / Likely Pathogenic· 129 VUS of 196 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.29LOEUF
pLI 0.989
Z-score 4.51
OE 0.13 (0.06–0.29)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.98Z-score
OE missense 0.88 (0.82–0.95)
482 obs / 546.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.06–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.82–0.95)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.16
0≤1.21.6
LoF obs/exp: 4 / 31.2Missense obs/exp: 482 / 546.1Syn Z: -1.97

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic1
VUS129
Likely Benign11
Benign2
Conflicting1
33
Pathogenic
1
Likely Pathogenic
129
VUS
11
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
7
26
0
33
Likely Pathogenic
0
0
1
0
1
VUS
4
119
6
0
129
Likely Benign
0
7
0
4
11
Benign
0
0
0
2
2
Conflicting
—1
Total4133336177

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

View in ClinVar →

Protein Context — Lollipop Plot

ZNRF3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ZNRF3-related neurodevelopmental disorder with macrocephaly

moderate
ADDominant NegativeAltered Gene Product Structure
Dev. Disorders
G2P ↗
frameshift variantmissense variantinframe deletion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The molecular genetics of adrenal cushing.
Vaduva P et al.·Hormones (Athens)
2024Review
Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling.
Boonsawat P et al.·Am J Hum Genet
2024
ZNRF3 in neurodevelopmental disorders: insights into Wnt signaling and therapeutic potential.
Dinle YYH et al.·Neurogenetics
2025Review
Epithelial WNT secretion drives niche escape of developing gastric cancer.
Lee J et al.·Mol Cancer
2025
Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-Analysis.
Liang YJ et al.·JAMA Ophthalmol
2024Meta-analysis
ZnRF3 induces apoptosis of gastric cancer cells by antagonizing Wnt and Hedgehog signaling.
Qin H et al.·Panminerva Med
2015
The role of R-spondins and their receptors in bone metabolism.
Shi GX et al.·Prog Biophys Mol Biol
2016Review
ZnRF3 Induces Apoptosis of Gastric Cancer Cells by Antagonizing Wnt and Hedgehog Signaling.
Qin H et al.·Cell Biochem Biophys
2015
Targeted Next Generation Sequencing molecular profiling and its clinical application in adrenocortical cancer.
Cioppi F et al.·Eur J Endocrinol
2024
Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.
Kschonsak YT et al.·Cell Chem Biol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools