SHARPIN
protein-codingSHANK associated RH domain interactor, the group of Linear ubiquitin chain assembly complex |Zinc fingers RANBP2-type
Gene summary
Enables polyubiquitin modification-dependent protein binding activity. Involved in defense response to bacterium; protein linear polyubiquitination; and regulation of signal transduction. Located in cytosol. Part of LUBAC complex. [provided by Alliance of Genome Resources, Jul 2025]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0968982
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0968982
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: The condition involves autoinflammation, with signs of immunodeficiency, and medical management (eg, with TNF inhibitors, IVIG, and corticosteroids) has been described as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SHARPIN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_030974.4. 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 | ||||
| missense | 67 | 5 | 72 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 3 | 3 | 6 | |||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 3 | 0 | 76 | 6 | 0 | 85 |
Highest pathogenic variant AF is 0.000002052385
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_112236.3 | 8 | MANE Select | |
| Ensembl | ENSP00000381698.2 | 8 | MANE Select | |
| Ensembl | ENSP00000352551.6 | 7 | Standard | |
| Ensembl | ENSP00000432355.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Necroptosis - Homo sapiens (human)
- NOD-like receptor signaling pathway - Homo sapiens (human)
- Signal Transduction
- Neuronal System
- TNFR1-induced NFkappaB signaling pathway
Biological Process
- mitochondrion organization
- I-kappaB kinase/NF-kappaB signaling
- brain development
- regulation of tumor necrosis factor-mediated signaling pathway
- apoptotic nuclear changes
Molecular Function
- ubiquitin-protein transferase activity
- protein binding
- polyubiquitin modification-dependent protein binding
- identical protein binding
- ubiquitin binding
Cellular Component
- cytosol
- postsynaptic density
- cell junction
- dendrite
- LUBAC complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000398712
- Coding exons
- 8
- Length
- 9492
- Individuals with no LoFs
- 124780
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 124796
- p
- 0.0000641
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0439 | 215 | 213 | 1.01 | 0.0000118 | 2361 |
| Missense (PolyPhen) | 53 | 61.239 | 0.86546 | 701 | ||
| Synonymous | -1.92 | 116 | 92.5 | 1.25 | 0.00000549 | 871 |
| Loss of Function | 1.63 | 10 | 17.3 | 0.577 | 8.17e-7 | 184 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| Latino/Admixed American | 0.000066 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000063 | 0.000062 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF- RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. {ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181}.;
Recessive Scores
- pRec
- 0.0834
Intolerance Scores
- LoFtool
- 0.359
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.91
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.922
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |