APPL1
protein-codingadaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1, the group of BAR-PH domain containing
Gene summary
The protein encoded by this gene has been shown to be involved in the regulation of cell proliferation, and in the crosstalk between the adiponectin signalling and insulin signalling pathways. The encoded protein binds many other proteins, including RAB5A, DCC, AKT2, PIK3CA, adiponectin receptors, and proteins of the NuRD/MeCP1 complex. This protein is found associated with endosomal membranes, but can be released by EGF and translocated to the nucleus. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~50.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014674
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014674
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014674
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0014674
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: ClinGen
*APPL1* was first reported in relation to apparent autosomal dominant diabetes in 2015 (Prudente et al., PMID: 26073777). Evidence supporting this gene-disease relationship includes case level data, segregation data, and experimental data. Summary of genetic and experimental evidence: 7.0 points. This gene- disease relationship was re-evaluated in October 2025. As a result of this re-evaluation, no further convincing genetic or experimental evidence supporting a gene-disease relationship is available in the literature. Moreover, Siriam et al (PMID: 40779032) reported a lack of enrichment of ultra-rare (i.e., MAF<1:10,000) protein-truncating and predicted-damaging missense variants in *APPL1* within a MODY testing cohort of 2,571 patients as compared to population controls (UKBiobank n=155,501 and n= 4,029 Non-Finnish Europeans from gnomAD v3.1.2 all p>0.05). Furthermore, *APPL1* pedigrees showed that more than 10% of family members aged 25 or older without diabetes carried the variant. This large-scale study evaluating gene-level burden tests in a MODY cohort (PMID: 40779032) provides strong evidence against *APPL1* pathogenicity for monogenic diabetes. As a result of this reevaluation, *APPL1* is refuted as a monogenic diabetes gene with the addition of new genetic evidence (PMID: 40779032). This classification was approved by the Monogenic Diabetes GCEP on February 13, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP11.
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to APPL1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012096.3. 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 | 7 | 31 | 3 | 41 | ||
| missense | 1 | 121 | 14 | 136 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 13 | 13 | ||||
| Total | 2 | 1 | 143 | 45 | 3 | 194 |
Highest pathogenic variant AF is 0.0000034339905
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036228.1 | 22 | MANE Select | |
| Ensembl | ENSP00000288266.3 | 22 | MANE Select | |
| Ensembl | ENSP00000406095.1 | 7 | Standard | |
| Ensembl | ENSP00000419644.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| appl1 | Danio rerio | Structure: whole organism Quality: edematous abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Longevity regulating pathway - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Colorectal cancer - Homo sapiens (human)
- Follicle Stimulating Hormone (FSH) signaling pathway
- Chromosomal and microsatellite instability in colorectal cancer
Biological Process
- cell cycle
- signal transduction
- cell population proliferation
- insulin receptor signaling pathway
- signaling
Molecular Function
- protein binding
- identical protein binding
- protein kinase B binding
- protein-containing complex binding
Cellular Component
- nucleus
- early endosome
- cytosol
- endosome membrane
- vesicle membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000288266
- Coding exons
- 22
- Length
- 45732
- Individuals with no LoFs
- 125627
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 121
- Defined
- 125748
- p
- 0.000481
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.716 | 329 | 368 | 0.895 | 0.0000193 | 4655 |
| Missense (PolyPhen) | 107 | 117.12 | 0.91356 | 1398 | ||
| Synonymous | 0.880 | 108 | 120 | 0.898 | 0.00000583 | 1284 |
| Loss of Function | 4.96 | 9 | 44.9 | 0.201 | 0.00000240 | 561 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00064 | 0.00062 | rare |
| Latino/Admixed American | 0.00019 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00023 | 0.00022 | rare |
| Finnish | 0.00020 | 0.00018 | rare |
| European (Non-Finnish) | 0.00076 | 0.00071 | rare |
| South Asian | 0.00040 | 0.00039 | rare |
| Other | 0.00051 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adapter protein that interacts with proteins involved in different cellular signaling pathways. Required for the regulation of cell proliferation in response to extracellular signals from an early endosomal compartment. Links Rab5 to nuclear signal transduction. Involved in the regulation of the insulin receptor signaling pathway. {ECO:0000269|PubMed:10490823, ECO:0000269|PubMed:15016378, ECO:0000269|PubMed:26073777}.;
- Disease
- DISEASE: Maturity-onset diabetes of the young 14 (MODY14) [MIM:616511]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:26073777}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.838
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 57.41
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.925
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |