APPL1

adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1, the group of BAR-PH domain containing

Basic information

Region (hg38): 3:57227725-57278105

Links

ENSG00000157500 ∙ NCBI:26060 ∙ OMIM:604299 ∙ HGNC:24035 ∙ Uniprot:Q9UKG1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• maturity-onset diabetes of the young type 14 (Strong), mode of inheritance: AD
• maturity-onset diabetes of the young (Supportive), mode of inheritance: AD
• maturity-onset diabetes of the young type 14 (Limited), mode of inheritance: Unknown
• monogenic diabetes (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Maturity-onset diabetes of the young, type 14	AD	General	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	Endocrine	26073777

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the APPL1 gene.

• not provided (100 variants)
• Inborn genetic diseases (23 variants)
• not specified (9 variants)
• Maturity-onset diabetes of the young type 14 (7 variants)
• APPL1-related condition (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the APPL1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	13	3	18
missense			37	4	2	43
nonsense		1				1
start loss						0
frameshift						0
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			1	1	2	4
non coding			12	23	22	57
Total	0	1	52	40	27

Highest pathogenic variant AF is 0.00000658

Variants in APPL1

This is a list of pathogenic ClinVar variants found in the APPL1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-57227733-G-C			Likely benign (Oct 21, 2018)
3-57227866-C-T			Benign (Sep 29, 2018)
3-57227888-C-A			Uncertain significance (Nov 16, 2022)
3-57227892-G-A		APPL1-related disorder	Benign (Dec 26, 2023)
3-57227919-G-C		not specified	Benign/Likely benign (Jan 26, 2024)
3-57227930-G-T		not specified	Uncertain significance (Jan 09, 2024)
3-57227933-C-G			Uncertain significance (Jun 25, 2023)
3-57227947-G-A			Likely benign (Apr 02, 2021)
3-57228000-C-T			Benign (Oct 05, 2018)
3-57235300-G-C			Likely benign (Aug 25, 2018)
3-57235547-T-C			Likely benign (Nov 24, 2023)
3-57235580-A-G		Maturity-onset diabetes of the young type 14	Benign (Jan 26, 2024)
3-57235628-G-C			Uncertain significance (May 05, 2022)
3-57235647-C-T			Uncertain significance (-)
3-57237533-A-G			Likely benign (Jan 23, 2023)
3-57237538-A-G		not specified • APPL1-related disorder	Benign (Jan 10, 2024)
3-57237885-G-A			Benign (Aug 17, 2018)
3-57238027-C-A			Likely benign (Aug 15, 2021)
3-57238050-T-C		Maturity-onset diabetes of the young type 14	Benign/Likely benign (Nov 19, 2023)
3-57238087-T-C		not specified • Maturity-onset diabetes of the young type 14 • APPL1-related disorder	Benign/Likely benign (Jan 01, 2024)
3-57238098-T-C			Likely benign (Jan 03, 2024)
3-57238111-G-A		Maturity-onset diabetes of the young type 14	Pathogenic (Jul 02, 2015)
3-57238122-C-T			Benign (Feb 01, 2024)
3-57238331-C-T			Likely benign (Sep 16, 2018)
3-57240449-GTCTT-G			Likely benign (Nov 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
APPL1	protein_coding	protein_coding	ENST00000288266	22	45732

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.795	0.205	125627	0	121	125748	0.000481

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.716	329	368	0.895	0.0000193	4655
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000835	0.000808
Ashkenazi Jewish	0.000103	0.0000992
East Asian	0.000227	0.000217
Finnish	0.000199	0.000185
European (Non-Finnish)	0.000763	0.000712
Middle Eastern	0.000227	0.000217
South Asian	0.000398	0.000392
Other	0.000510	0.000489

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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;Caspase activation via extrinsic apoptotic signalling pathway;Apoptosis;Programmed Cell Death;AndrogenReceptor;EGFR1;Coregulation of Androgen receptor activity;Ligand-independent caspase activation via DCC;FSH (Consensus)

Intolerance Scores

• loftool: 0.838
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.41

Haploinsufficiency Scores

• pHI: 0.342
• hipred: Y
• hipred_score: 0.651
• ghis: 0.613

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.925

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Appl1
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: appl1
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: edematous

Gene ontology

• Biological process: cell cycle;signal transduction;cell population proliferation;insulin receptor signaling pathway;signaling;regulation of glucose import;extrinsic apoptotic signaling pathway in absence of ligand;regulation of protein localization to plasma membrane
• Cellular component: nucleus;early endosome;cytosol;endosome membrane;vesicle membrane;early endosome membrane;extracellular exosome
• Molecular function: protein binding;identical protein binding;protein kinase B binding;protein-containing complex binding