NPLOC4

Chr 17

NPL4 homolog, ubiquitin recognition factor

Also known as: NPL4

NCBI Gene: 55666ENSG00000182446UniProt: Q8TAT6

Predicted to enable ubiquitin binding activity and ubiquitin protein ligase binding activity. Predicted to contribute to K48-linked polyubiquitin modification-dependent protein binding activity and K63-linked polyubiquitin modification-dependent protein binding activity. Involved in negative regulation of RIG-I signaling pathway; negative regulation of type I interferon production; and proteolysis involved in protein catabolic process. Located in nucleus. Part of UFD1-NPL4 complex and VCP-NPL4-UFD1 AAA ATPase complex. [provided by Alliance of Genome Resources, Jul 2025]

0
Active trials
0
Pathogenic / LP
0
ClinVar variants
5
Pubs (1 yr)
3.2
Missense Z· constrained
0.13
LOEUF· LoF intolerant
Clinical Summary— NPLOC4
⚡
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.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.13LOEUF
pLI 1.000
Z-score 5.36
OE 0.03 (0.01–0.13)
Highly constrained

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

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.
3.20Z-score
OE missense 0.52 (0.46–0.59)
185 obs / 354.6 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.03 (0.01–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.46–0.59)
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.1.05
0≤1.21.6
LoF obs/exp: 1 / 35.4Missense obs/exp: 185 / 354.6Syn Z: -0.48

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

NPLOC4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

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
Key Publications
Landmark & review papers · by relevance
PubMed
Copper metabolism in cell death and autophagy.
Xue Q et al.·Autophagy
2023Review
VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.
Wang Z et al.·Autophagy
2024
CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies.
Wang D et al.·Cancer Discov
2021
Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking.
He W et al.·Nat Commun
2025Meta-analysis
A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus.
Plotnikov D et al.·Hum Genet
2019
NPLOC4 Inhibition Remodels Tumor Microenvironment via M2-to-M1 Macrophage Reprogramming and Boosts Anti-PD-1 Response in Liver Cancer.
Gao X et al.·Int J Biol Sci
2026Functional
Genome-wide association analyses identify 139 loci associated with macular thickness in the UK Biobank cohort.
Gao XR et al.·Hum Mol Genet
2019Cohort
In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination.
Ghosh S et al.·J Vis Exp
2026
Macular thickness varies with age-related macular degeneration genetic risk variants in the UK Biobank cohort.
Kaye RA et al.·Sci Rep
2021Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗

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