ZNRF1

Chr 16

zinc and ring finger 1

Also known as: NIN283

NCBI Gene: 84937ENSG00000186187UniProt: Q8ND25

This gene encodes an E3 ubiquitin-protein ligase that plays a role in neural-cell differentiation. Overexpression of this gene causes neurite-like elongation. The encoded protein contains both a zinc finger and a RING finger motif and is localized in the endosome/lysosome compartment, indicating that it may be involved in ubiquitin-mediated protein modification, and in synaptic vessicle membranes in neurons. [provided by RefSeq, Feb 2012]

0
Active trials
26
Pathogenic / LP
84
ClinVar variants
3
Pubs (1 yr)
0.9
Missense Z
0.39
LOEUF
Clinical Summary— ZNRF1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 50 VUS of 84 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.
0.39LOEUF
pLI 0.906
Z-score 2.56
OE 0.00 (0.00–0.39)
Highly constrained

More LoF-intolerant than ~75% 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.
0.92Z-score
OE missense 0.75 (0.62–0.90)
79 obs / 105.7 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.0.00 (0.00–0.39)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.62–0.90)
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.0.91
0≤1.21.6
LoF obs/exp: 0 / 7.6Missense obs/exp: 79 / 105.7Syn Z: 0.46
DN
0.4388th %ile
GOF
0.4183th %ile
LOF
0.72top 10%

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

LOFprediction above median · LOEUF 0.39

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

84 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic1
VUS50
Likely Benign2
Benign6
25
Pathogenic
1
Likely Pathogenic
50
VUS
2
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
25
0
25
Likely Pathogenic
0
0
1
0
1
VUS
0
27
23
0
50
Likely Benign
0
1
0
1
2
Benign
0
0
6
0
6
Total02855184

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

View in ClinVar →

Protein Context — Lollipop Plot

ZNRF1 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 2 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Myeloid ZNRF1 suppresses autoimmune demyelination and neuroinflammation by regulating MHC-II-mediated T cell activation.
Chang YC et al.·J Neuroinflammation
2025Open Access
ZNRF1-dependent regulation of AKT activity modulates Nav subcellular localization and AIS position in neurons to regulate fear-related behaviour.
Ohno M et al.·J Biochem
2025
The essential role of E3 ubiquitin ligases in the pathogenesis of neurodevelopmental and psychiatric disorders: Cul3, Cul4, Ube3a, and ZNRF1.
Ohno M et al.·Biochem Biophys Res Commun
2025
Myricanol represses renal fibrosis by activating TFAM and ZNRF1 to inhibit tubular epithelial cells ferroptosis.
Zheng M et al.·Eur J Pharmacol
2024
The Drosophila ZNRF1/2 homologue, detour, interacts with HOPS complex and regulates autophagy.
Nicolson S et al.·Commun Biol
2024Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients