SCG5
protein-codingsecretogranin V, the group of Granins
Gene summary
This gene encodes a secreted chaperone protein that prevents the aggregation of other secreted proteins, including proteins that are associated with neurodegenerative and metabolic disease. The encoded protein may be best known for its role in the trafficking and activation of prohormone convertase PC2 (encoded by Gene ID: 5126). Phosphorylation of the encoded protein has been shown to have an inhibitory effect on its chaperone function. This gene also produces a ARHGAP11A-SCG5 readthrough transcript and ARHGAP11A-SCG5 protein. [provided by RefSeq, Feb 2019]
- SGNE1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~55.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011023
Submitter: ClinGen
SCG5 was first reported in relation to autosomal dominant Hereditary Mixed Polyposis Syndrome (HMPS; MONDO:0010950) in 2012 (Jaeger et al., PMID: 22561515), following genomic characterization of six families of Ashkenazi ancestry previously described with HMPS (PMIDs: 9024286, 10092300, 12696020, 18084292). HMPS is an inherited colorectal polyposis disorder characterized by a mixture of hyperplastic, atypical juvenile, and adenomatous polyps with increased colorectal cancer risk. Four variants, including the Ashkenazi founder duplication, have been reported in 19 probands across 9 publications (PMIDs: 9024286, 10092300, 12696020, 18084292, 21128281, 22561515, 24586997, 26493165, 29804199), with additional reports in the literature, but the maximum score for genetic evidence (12 points) has already been reached (PMIDs: 25992589, 26947005, 28242209, 27984123). It is important to note pathogenic mechanism is not attributable to loss of SCG5 function; rather, duplications spanning the 3′ end of SCG5 extend into the upstream regulatory elements of GREM1 lead to ectopic and increased GREM1 expression in colonic epithelium. Expression studies in duplication carriers confirm no effect on SCG5 but allele-specific overexpression of GREM1 (PMIDs: 22561515, 26493165). Experimental evidence (3.6 points) further supports this mechanism: GREM1 overexpression in human tissue and mouse models recapitulates the HMPS phenotype, while knockout reduces polyp burden (PMID: 25419707). In summary, duplications involving the SCG5-GREM1 locus are definitively associated (15.6 points) with autosomal dominant HMPS, due to GREM1 dysregulation. This gene-disease pair was curated on 08/28/2026 by the Hereditary Cancer GCEP (SOP Version 12).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SCG5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001144757.3. 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 | 9 | 10 | |||
| missense | 27 | 27 | ||||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 31 | 9 | 0 | 40 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001138229.1 | 5 | MANE Select | |
| Ensembl | ENSP00000300175.4 | 5 | MANE Select | |
| RefSeq | NP_001381207.1 | 4 | Standard | |
| RefSeq | NP_001381208.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| scg5 | Danio rerio | Structure: ventricular system Quality: hydrocephalic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- intracellular protein transport
- neuropeptide signaling pathway
- peptide hormone processing
- negative regulation of catalytic activity
- regulation of hormone secretion
Molecular Function
- enzyme inhibitor activity
- protein binding
- GTP binding
- unfolded protein binding
Cellular Component
- extracellular region
- secretory granule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000300175
- Coding exons
- 5
- Length
- 55423
- Individuals with no LoFs
- 124599
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 40
- Defined
- 124639
- p
- 0.000160
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.613 | 97 | 116 | 0.839 | 0.00000590 | 1385 |
| Missense (PolyPhen) | 35 | 52.2 | 0.6705 | 627 | ||
| Synonymous | -0.471 | 45 | 41.2 | 1.09 | 0.00000194 | 413 |
| Loss of Function | 1.02 | 8 | 11.8 | 0.678 | 7.44e-7 | 117 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00026 | rare |
| Latino/Admixed American | 0.000088 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00080 | 0.00080 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a molecular chaperone for PCSK2/PC2, preventing its premature activation in the regulated secretory pathway. Binds to inactive PCSK2 in the endoplasmic reticulum and facilitates its transport from there to later compartments of the secretory pathway where it is proteolytically matured and activated. Also required for cleavage of PCSK2 but does not appear to be involved in its folding. Plays a role in regulating pituitary hormone secretion. The C-terminal peptide inhibits PCSK2 in vitro. {ECO:0000269|PubMed:7913882}.;
Recessive Scores
- pRec
- 0.169
Intolerance Scores
- LoFtool
- 0.488
- RVIS EVS
- -0.21
- RVIS percentile EVS
- 38.28
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.603
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |