ABL1

ABL proto-oncogene 1, non-receptor tyrosine kinase, the group of Abl family tyrosine kinases|SH2 domain containing

Basic information

Region (hg38): 9:130713042-130887675

Previous symbols: [ "ABL" ]

Links

ENSG00000097007 ∙ NCBI:25 ∙ OMIM:189980 ∙ HGNC:76 ∙ Uniprot:P00519 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital heart defects and skeletal malformations syndrome (Strong), mode of inheritance: AD
• congenital heart defects and skeletal malformations syndrome (Strong), mode of inheritance: AD
• connective tissue disorder (Moderate), mode of inheritance: AD
• congenital heart defects and skeletal malformations syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital heart defects and skeletal malformations syndrome	AD	Cardiovascular	The condition can include adult-onset aortic root dilation, and awareness may allow early identification and management	Cardiovascular; Musculoskeletal	28288113

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ABL1 gene.

• not provided (341 variants)
• Inborn genetic diseases (32 variants)
• Congenital heart defects and skeletal malformations syndrome (26 variants)
• not specified (24 variants)
• ABL1-related condition (7 variants)
• Chronic myelogenous leukemia, BCR-ABL1 positive;Congenital heart defects and skeletal malformations syndrome (3 variants)
• Congenital heart defects and skeletal malformations syndrome;Chronic myelogenous leukemia, BCR-ABL1 positive (2 variants)
• Chronic myelogenous leukemia, BCR-ABL1 positive (2 variants)
• Microcephaly (1 variants)
• ABL1-Related Disorder (1 variants)
• Lymphoblastic leukemia, acute, with lymphomatous features (1 variants)
• Abnormal skeletal morphology;Congenital heart disease;Failure to thrive (1 variants)
• ABL1-related congenital heart defects and skeletal malformations syndrome (1 variants)
• Leukemia, Philadelphia chromosome-positive, resistant to imatinib (1 variants)
• Congenital heart disease;Abnormal skeletal morphology;Failure to thrive (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ABL1 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			1	90	37	128
missense	3	13	103	69	31	219
nonsense			1			1
start loss						0
frameshift			2			2
inframe indel			3			3
splice donor/acceptor (+/-2bp)			1			1
splice region			5	2	2	9
non coding				20	2	22
Total	3	13	111	179	70

Variants in ABL1

This is a list of pathogenic ClinVar variants found in the ABL1 region.

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

Position	Type	Phenotype	Significance	ClinVar
9-130714335-G-A			Likely benign (Sep 21, 2022)
9-130714339-A-G		Inborn genetic diseases	Uncertain significance (Jan 16, 2022)
9-130714345-T-C			Likely benign (Feb 03, 2022)
9-130714348-G-A			Uncertain significance (Jul 26, 2023)
9-130714357-G-A			Uncertain significance (Dec 01, 2023)
9-130714376-C-T			Likely benign (Nov 07, 2023)
9-130714424-G-A			Likely benign (Jul 28, 2023)
9-130714427-T-A			Likely benign (Dec 22, 2021)
9-130714468-C-A			Likely benign (Nov 10, 2023)
9-130714468-C-T			Likely benign (Aug 11, 2023)
9-130714474-T-G			Likely benign (Jan 18, 2024)
9-130854047-C-G			Likely benign (Aug 31, 2022)
9-130854050-C-G			Likely benign (Jan 18, 2024)
9-130854050-C-T			Likely benign (Apr 10, 2023)
9-130854052-T-C			Likely benign (Jun 24, 2023)
9-130854062-A-G			Likely benign (Dec 02, 2022)
9-130854076-G-A			Likely benign (Oct 14, 2023)
9-130854093-T-G			Uncertain significance (Aug 24, 2021)
9-130854100-C-G			Uncertain significance (Jan 10, 2020)
9-130854112-G-A		not specified • ABL1-related disorder	Benign (Dec 11, 2023)
9-130854119-C-T			Likely benign (Dec 31, 2023)
9-130854120-G-A			Uncertain significance (Nov 25, 2023)
9-130854124-G-A			Benign (Jul 25, 2022)
9-130854127-G-C		Congenital heart defects and skeletal malformations syndrome	Likely pathogenic (Jun 24, 2022)
9-130854150-G-A			Likely benign (Oct 10, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ABL1	protein_coding	protein_coding	ENST00000372348	11	173730

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000172	125744	0	4	125748	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.56	523	716	0.731	0.0000453	7454
Missense in Polyphen		259	432.88	0.59831		4507
Synonymous	-0.471	325	314	1.03	0.0000217	2393
Loss of Function	5.74	3	44.1	0.0680	0.00000246	496

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000869	0.0000869
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000881	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717' (PubMed:28428613). ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin- associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Regulates T-cell differentiation in a TBX21- dependent manner. Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity (By similarity). {ECO:0000250|UniProtKB:P00520, ECO:0000269|PubMed:10391250, ECO:0000269|PubMed:11971963, ECO:0000269|PubMed:12379650, ECO:0000269|PubMed:12531427, ECO:0000269|PubMed:12672821, ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:15556646, ECO:0000269|PubMed:15657060, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16424036, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:16943190, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:17623672, ECO:0000269|PubMed:18328268, ECO:0000269|PubMed:18945674, ECO:0000269|PubMed:19891780, ECO:0000269|PubMed:20357770, ECO:0000269|PubMed:20417104, ECO:0000269|PubMed:28428613, ECO:0000269|PubMed:9037071, ECO:0000269|PubMed:9144171, ECO:0000269|PubMed:9461559}.
• Disease: DISEASE: Leukemia, chronic myeloid (CML) [MIM:608232]: A clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B-lymphoid, and sometimes T-lymphoid cells, but not marrow fibroblasts. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Note=A chromosomal aberration involving ABL1 has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).; DISEASE: Congenital heart defects and skeletal malformations syndrome (CHDSKM) [MIM:617602]: An autosomal dominant disorder characterized by congenital heart disease with atrial and ventricular septal defects, variable skeletal abnormalities, and failure to thrive. Skeletal defects include pectus excavatum, scoliosis, and finger contractures. Some patient exhibit joint laxity. {ECO:0000269|PubMed:28288113}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Chronic myeloid leukemia - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Cell cycle - Homo sapiens (human);Viral myocarditis - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Axon guidance - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Shigellosis - Homo sapiens (human);Pathogenic Escherichia coli infection - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Imatinib Pathway, Pharmacokinetics/Pharmacodynamics;Cell Cycle;miRNA Regulation of DNA Damage Response;miRNAs involved in DNA damage response;TP53 Network;Integrated Breast Cancer Pathway;Regulation of Microtubule Cytoskeleton;Pathogenic Escherichia coli infection;Retinoblastoma (RB) in Cancer;ATM Signaling Pathway;Apoptosis-related network due to altered Notch3 in ovarian cancer;Imatinib and Chronic Myeloid Leukemia;Ras Signaling;EGF-EGFR Signaling Pathway;ErbB Signaling Pathway;DNA Damage Response;DNA Damage Response (only ATM dependent);Developmental Biology;RUNX2 regulates osteoblast differentiation;HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);RUNX2 regulates bone development;Transcriptional regulation by RUNX2;DNA Repair;Signal Transduction;Gene expression (Transcription);DNA Double-Strand Break Repair;tumor suppressor arf inhibits ribosomal biogenesis;lissencephaly gene (lis1) in neuronal migration and development;cell cycle: g1/s check point;Generic Transcription Pathway;Alpha6Beta4Integrin;Homology Directed Repair;Factors involved in megakaryocyte development and platelet production;RNA Polymerase II Transcription;Fcgamma receptor (FCGR) dependent phagocytosis;TCR;Innate Immune System;Immune System;RHO GTPases Activate WASPs and WAVEs;Cyclin D associated events in G1;G1 Phase;p73 transcription factor network;KitReceptor;Mitotic G1-G1/S phases;CDO in myogenesis;Myogenesis;RHO GTPase Effectors;Signaling by Rho GTPases;atm signaling pathway;EGFR1;Hemostasis;Validated transcriptional targets of TAp63 isoforms;Regulation of actin dynamics for phagocytic cup formation;Posttranslational regulation of adherens junction stability and dissassembly;Signaling by ROBO receptors;Axon guidance;RUNX1 regulates transcription of genes involved in differentiation of HSCs;Cell Cycle;Role of ABL in ROBO-SLIT signaling;Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks;DNA Double Strand Break Response;Cell Cycle, Mitotic;Transcriptional regulation by RUNX1;Neurotrophic factor-mediated Trk receptor signaling;Regulation of Telomerase;PDGFR-beta signaling pathway;Regulation of retinoblastoma protein;ATM pathway;Lissencephaly gene (LIS1) in neuronal migration and development;p53 pathway (Consensus)

Recessive Scores

• pRec: 0.609

Intolerance Scores

• loftool: 0.00331
• rvis_EVS: -1.63
• rvis_percentile_EVS: 2.85

Haploinsufficiency Scores

• pHI: 0.993
• hipred: Y
• hipred_score: 0.825
• ghis: 0.577

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Abl1
• 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); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; embryo phenotype; respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); craniofacial phenotype; vision/eye phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype

Gene ontology

• Biological process: mitotic cell cycle;neural tube closure;B-1 B cell homeostasis;positive regulation of protein phosphorylation;B cell proliferation involved in immune response;transitional one stage B cell differentiation;mismatch repair;regulation of transcription, DNA-templated;cellular protein modification process;protein phosphorylation;autophagy;cellular response to DNA damage stimulus;DNA damage induced protein phosphorylation;response to oxidative stress;cell cycle arrest;epidermal growth factor receptor signaling pathway;positive regulation of cytosolic calcium ion concentration;integrin-mediated signaling pathway;intrinsic apoptotic signaling pathway in response to DNA damage;post-embryonic development;regulation of autophagy;positive regulation of endothelial cell migration;peptidyl-tyrosine phosphorylation;cerebellum morphogenesis;negative regulation of cell-cell adhesion;microspike assembly;actin cytoskeleton organization;regulation of endocytosis;cell differentiation;regulation of cell adhesion;negative regulation of BMP signaling pathway;regulation of axon extension;regulation of microtubule polymerization;regulation of Cdc42 protein signal transduction;regulation of actin cytoskeleton organization;positive regulation of osteoblast proliferation;substrate adhesion-dependent cell spreading;cellular response to oxidative stress;platelet-derived growth factor receptor-beta signaling pathway;peptidyl-tyrosine autophosphorylation;Fc-gamma receptor signaling pathway involved in phagocytosis;neuropilin signaling pathway;regulation of cell population proliferation;signal transduction in response to DNA damage;positive regulation of apoptotic process;positive regulation of I-kappaB kinase/NF-kappaB signaling;negative regulation of I-kappaB kinase/NF-kappaB signaling;endothelial cell migration;establishment of protein localization;regulation of T cell differentiation;negative regulation of mitotic cell cycle;positive regulation of mitotic cell cycle;alpha-beta T cell differentiation;protein autophosphorylation;spleen development;thymus development;collateral sprouting;positive regulation of peptidyl-tyrosine phosphorylation;activated T cell proliferation;T cell receptor signaling pathway;B cell receptor signaling pathway;neuromuscular process controlling balance;positive regulation of muscle cell differentiation;positive regulation of release of sequestered calcium ion into cytosol;positive regulation of oxidoreductase activity;negative regulation of ubiquitin-protein transferase activity;positive regulation of stress fiber assembly;mitochondrial depolarization;positive regulation of focal adhesion assembly;Bergmann glial cell differentiation;neuroepithelial cell differentiation;cellular response to hydrogen peroxide;negative regulation of ERK1 and ERK2 cascade;positive regulation of ERK1 and ERK2 cascade;cellular response to lipopolysaccharide;negative regulation of protein serine/threonine kinase activity;cardiovascular system development;positive regulation of cell migration involved in sprouting angiogenesis;actin filament branching;positive regulation of substrate adhesion-dependent cell spreading;positive regulation of interleukin-2 secretion;negative regulation of long-term synaptic potentiation;negative regulation of phospholipase C activity;positive regulation of neuron death;regulation of hematopoietic stem cell differentiation;positive regulation of interferon-gamma secretion;regulation of extracellular matrix organization;cellular response to dopamine;positive regulation of microtubule binding;positive regulation of actin filament binding;regulation of modification of synaptic structure;positive regulation blood vessel branching;activation of protein kinase C activity;positive regulation of Wnt signaling pathway, planar cell polarity pathway;regulation of cell motility;regulation of actin cytoskeleton reorganization;positive regulation of actin cytoskeleton reorganization;negative regulation of endothelial cell apoptotic process;negative regulation of cellular senescence;regulation of response to DNA damage stimulus
• Cellular component: nucleus;nucleoplasm;nucleolus;cytoplasm;mitochondrion;cytosol;actin cytoskeleton;nuclear body;dendrite;cell leading edge;nuclear membrane;protein-containing complex;neuronal cell body;perinuclear region of cytoplasm;postsynapse
• Molecular function: magnesium ion binding;phosphotyrosine residue binding;DNA binding;actin monomer binding;nicotinate-nucleotide adenylyltransferase activity;protein kinase activity;protein tyrosine kinase activity;non-membrane spanning protein tyrosine kinase activity;protein kinase C binding;protein binding;ATP binding;protein C-terminus binding;kinase activity;SH3 domain binding;syntaxin binding;manganese ion binding;neuropilin binding;SH2 domain binding;ephrin receptor binding;actin filament binding;mitogen-activated protein kinase binding;proline-rich region binding