APH1B
protein-codingaph-1 homolog B, gamma-secretase subunit
Gene summary
This gene encodes a multi-pass transmembrane protein that is a functional component of the gamma-secretase complex, which also contains presenilin and nicastrin. This protein represents a stabilizing cofactor for the presenilin holoprotein in the complex. The gamma-secretase complex catalyzes the cleavage of integral proteins such as notch receptors and beta-amyloid precursor protein. [provided by RefSeq, Sep 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.1 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 APH1B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_031301.4. 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 | 30 | 30 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 32 | 1 | 0 | 33 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_112591.2 | 6 | MANE Select | |
| Ensembl | ENSP00000261879.5 | 6 | MANE Select | |
| RefSeq | NP_001139118.1 | 5 | Standard | |
| Ensembl | ENSP00000369697.4 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| aph1b | Danio rerio | Structure: post-vent region Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Alzheimer,s disease - Homo sapiens (human)
- Notch signaling pathway - Homo sapiens (human)
- Notch Signaling Pathway
- Notch Signaling Pathway
- Notch Signaling Pathway
Biological Process
- Notch signaling pathway
- Notch receptor processing
- locomotory behavior
- protein processing
- Notch receptor processing, ligand-dependent
Molecular Function
- endopeptidase activity
- protein binding
- peptidase activity
Cellular Component
- endoplasmic reticulum
- plasma membrane
- integral component of plasma membrane
- endosome membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261879
- Coding exons
- 6
- Length
- 33109
- Individuals with no LoFs
- 125697
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 51
- Defined
- 125748
- p
- 0.000203
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.180 | 147 | 141 | 1.04 | 0.00000693 | 1654 |
| Missense (PolyPhen) | 72 | 58.693 | 1.2267 | 701 | ||
| Synonymous | -0.390 | 62 | 58.2 | 1.06 | 0.00000308 | 528 |
| Loss of Function | -0.533 | 15 | 12.9 | 1.16 | 7.93e-7 | 137 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00018 | rare |
| Latino/Admixed American | 0.00013 | 0.00012 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00027 | 0.00025 | rare |
| South Asian | 0.00021 | 0.00020 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A. {ECO:0000269|PubMed:12297508}.;
Recessive Scores
- pRec
- 0.172
Intolerance Scores
- LoFtool
- 0.870
- RVIS EVS
- 0.53
- RVIS percentile EVS
- 80.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.240
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |