NPLOC4
protein-codingNPL4 homolog, ubiquitin recognition factor, the group of Zinc fingers
Gene summary
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 protein catabolic process. Located in nucleoplasm. Part of UFD1-NPL4 complex and VCP-NPL4-UFD1 AAA ATPase complex. [provided by Alliance of Genome Resources, Jun 2026]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~91.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NPLOC4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017921.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 1 | 2 | 4 | ||
| missense | 61 | 4 | 1 | 66 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 0 | 67 | 5 | 3 | 75 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060391.2 | 17 | MANE Select | |
| Ensembl | ENSP00000331487.5 | 17 | MANE Select | |
| RefSeq | NP_001356627.1 | 17 | Standard | |
| RefSeq | NP_001424915.1 | 16 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein processing in endoplasmic reticulum - Homo sapiens (human)
- DNA Repair
- Translesion Synthesis by POLH
- Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template
- DNA Damage Bypass
Biological Process
- ubiquitin-dependent protein catabolic process
- Golgi organization
- ubiquitin-dependent ERAD pathway
- retrograde protein transport, ER to cytosol
- negative regulation of type I interferon production
Molecular Function
- protein binding
- ubiquitin protein ligase binding
- ubiquitin binding
- metal ion binding
Cellular Component
- nucleus
- nucleoplasm
- endoplasmic reticulum
- cytosol
- VCP-NPL4-UFD1 AAA ATPase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000331134
- Coding exons
- 17
- Length
- 91583
- Individuals with no LoFs
- 124634
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 124638
- p
- 0.0000160
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.20 | 185 | 355 | 0.522 | 0.0000209 | 3975 |
| Missense (PolyPhen) | 42 | 141.4 | 0.29704 | 1562 | ||
| Synonymous | -0.479 | 153 | 146 | 1.05 | 0.0000100 | 1133 |
| Loss of Function | 5.36 | 1 | 35.4 | 0.0283 | 0.00000183 | 407 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000027 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope (By similarity). Acts as a negative regulator of type I interferon production via the complex formed with VCP and UFD1, which binds to DDX58/RIG-I and recruits RNF125 to promote ubiquitination and degradation of DDX58/RIG-I (PubMed:26471729). {ECO:0000250|UniProtKB:Q9ES54, ECO:0000269|PubMed:26471729}.;
Intolerance Scores
- RVIS EVS
- -0.71
- RVIS percentile EVS
- 14.57
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.727
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |