APOA1

apolipoprotein A1, the group of Apolipoproteins

Basic information

Region (hg38): 11:116835751-116837622

Links

ENSG00000118137 ∙ NCBI:335 ∙ OMIM:107680 ∙ HGNC:600 ∙ Uniprot:P02647 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial visceral amyloidosis (Strong), mode of inheritance: AD
• apolipoprotein A-I deficiency (Supportive), mode of inheritance: AD
• AApoAI amyloidosis (Supportive), mode of inheritance: AD
• familial visceral amyloidosis (Definitive), mode of inheritance: AD
• familial visceral amyloidosis (Strong), mode of inheritance: AD
• hypoalphalipoproteinemia, primary, 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyloidosis, hereditary systemic 3; Hypoalphalipoproteinemia, primary 2	AD/AR	Cardiovascular; Endocrine; Gastrointestinal; Pharmacogenomic	In Hypoalphalipoproteinemia, primary 2, intervention to decrease risk factors contributing to cardiovascular disease (eg, CAD and stroke), as well as early surveillance and intervention in the case of findings such as CAD, may be beneficial; In Hereditary amyloidosis, individuals may manifest with sequelae affecting multiple organ systems, and awareness may allow early diagnossi and medical management (eg, related to endocrine or renal insufficiency); Liver transplantation can correct the underlying metabolic defect	Cardiovascular; Endocrine; Dermatologic; Gastrointestinal; Ophthalmologic; Renal	4304452; 7430351; 6776144; 7249374; 7080131; 7078608; 6818131; 6308458; 6131168; 6401735; 6401735; 3118360; 3141894; 2512329; 2512329; 1901417; 1502149; 8240372; 8282791; 7981179; 8675681; 9514407; 9916936; 10487826; 9931341; 12270762; 12050338; 16023124; 17991432; 21122686; 21443680; 21875686; 29446975; 30665372
Though manifestations have been described in adults, surveillance and interventions should likely begin in the pediatric period; Hypoalphalipoproteinemia, primary, 2, intermediate has not been described as involving cardiovascular risk

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the APOA1 gene.

• not provided (6 variants)
• Familial amyloid polyneuropathy, Iowa type (2 variants)
• Hypoalphalipoproteinemia, primary, 2 (1 variants)
• Hypoalphalipoproteinemia, primary, 2;Hypoalphalipoproteinemia, primary, 2, intermediate;Familial visceral amyloidosis, Ostertag type (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the APOA1 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	70		72
missense	4	2	121	2	1	130
nonsense	2	2	4			8
start loss						0
frameshift		2	1			3
inframe indel			1			1
splice donor/acceptor (+/-2bp)			1			1
splice region			3	6		9
non coding			3	16	9	28
Total	6	6	133	88	10

Highest pathogenic variant AF is 0.00000657

Variants in APOA1

This is a list of pathogenic ClinVar variants found in the APOA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-116835789-G-C		Hypoalphalipoproteinemia, primary, 1 • Familial visceral amyloidosis, Ostertag type • Hypoalphalipoproteinemia, primary, 2, intermediate • not specified • Hypoalphalipoproteinemia, primary, 2	Benign (Jun 25, 2023)
11-116835791-G-A		Familial visceral amyloidosis, Ostertag type • Hypoalphalipoproteinemia, primary, 1	Likely benign (Jan 13, 2018)
11-116835792-GGCGGC-G		not specified	Uncertain significance (Jun 18, 2023)
11-116835815-G-GTGT			Uncertain significance (Jan 19, 2024)
11-116835822-G-C		Cardiovascular phenotype	Uncertain significance (Jan 17, 2024)
11-116835823-C-A		Cardiovascular phenotype	Uncertain significance (Dec 21, 2023)
11-116835823-C-T			Likely benign (Oct 05, 2021)
11-116835833-T-C			Uncertain significance (Aug 07, 2022)
11-116835835-C-T			Likely benign (Dec 15, 2023)
11-116835840-C-G		Cardiovascular phenotype	Uncertain significance (Feb 11, 2023)
11-116835841-G-A			Likely benign (Jan 02, 2024)
11-116835841-G-C			Likely benign (Jan 11, 2022)
11-116835843-G-A		Cardiovascular phenotype	Uncertain significance (Sep 24, 2023)
11-116835846-C-T		Cardiovascular phenotype	Uncertain significance (Dec 02, 2023)
11-116835847-G-A		Cardiovascular phenotype	Likely benign (Jan 30, 2023)
11-116835851-A-C			Uncertain significance (Jan 17, 2023)
11-116835852-G-A		Cardiovascular phenotype	Likely benign (Jan 13, 2023)
11-116835860-A-T		not specified • Cardiovascular phenotype	Uncertain significance (May 24, 2022)
11-116835871-C-G			Uncertain significance (May 12, 2022)
11-116835880-G-A		Cardiovascular phenotype	Likely benign (Feb 18, 2021)
11-116835880-G-C		Hypoalphalipoproteinemia, primary, 1 • Familial visceral amyloidosis, Ostertag type • not specified • Cardiovascular phenotype • Hypoalphalipoproteinemia, primary, 2, intermediate • Hypoalphalipoproteinemia, primary, 2	Benign/Likely benign (Jan 31, 2024)
11-116835886-C-G		Cardiovascular phenotype • Familial visceral amyloidosis, Ostertag type;Hypoalphalipoproteinemia, primary, 2;Hypoalphalipoproteinemia, primary, 2, intermediate	Likely benign (Jan 04, 2024)
11-116835888-G-T		Cardiovascular phenotype	Uncertain significance (May 10, 2022)
11-116835898-G-A			Likely benign (Jun 09, 2023)
11-116835901-G-A			Likely benign (Jan 24, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
APOA1	protein_coding	protein_coding	ENST00000236850	3	2200

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000549	0.718	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.510	135	153	0.884	0.00000779	1740
Missense in Polyphen		35	43.341	0.80754		556
Synonymous	-0.839	80	71.0	1.13	0.00000386	523
Loss of Function	0.879	6	8.82	0.680	3.84e-7	96

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000267	0.0000264
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT). As part of the SPAP complex, activates spermatozoa motility. {ECO:0000269|PubMed:1909888}.
• Disease: DISEASE: High density lipoprotein deficiency 2 (HDLD2) [MIM:604091]: Inherited as autosomal dominant trait. It is characterized by moderately low HDL cholesterol, predilection toward premature coronary artery disease (CAD) and a reduction in cellular cholesterol efflux. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: High density lipoprotein deficiency 1 (HDLD1) [MIM:205400]: Recessive disorder characterized by absence of high density lipoprotein (HDL) cholesterol from plasma, accumulation of cholesteryl esters, premature coronary artery disease (CAD), hepatosplenomegaly, recurrent peripheral neuropathy and progressive muscle wasting and weakness. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=APOA1 mutations may be involved in the pathogenesis of amyloid polyneuropathy-nephropathy Iowa type, also known as amyloidosis van Allen type or familial amyloid polyneuropathy type III (PubMed:3142462 and PubMed:2123470). The clinical picture is dominated by neuropathy in the early stages of the disease and nephropathy late in the course. Death is due in most cases to renal amyloidosis.; DISEASE: Amyloidosis 8 (AMYL8) [MIM:105200]: A form of hereditary generalized amyloidosis. Clinical features include extensive visceral amyloid deposits, renal amyloidosis resulting in nephrotic syndrome, arterial hypertension, hepatosplenomegaly, cholestasis, petechial skin rash. There is no involvement of the nervous system. {ECO:0000269|PubMed:1502149, ECO:0000269|PubMed:2123470, ECO:0000269|PubMed:3142462, ECO:0000269|PubMed:8208902}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Fat digestion and absorption - Homo sapiens (human);Vitamin digestion and absorption - Homo sapiens (human);African trypanosomiasis - Homo sapiens (human);Cholesterol metabolism - Homo sapiens (human);PPAR signaling pathway - Homo sapiens (human);Statin Pathway, Pharmacodynamics;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate Metabolism;Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha);Human Complement System;PPAR Alpha Pathway;Nuclear Receptors Meta-Pathway;PPAR signaling pathway;Statin Pathway;Signaling by GPCR;Signal Transduction;Metabolism of fat-soluble vitamins;mechanism of gene regulation by peroxisome proliferators via ppara;Chylomicron assembly;Vesicle-mediated transport;HDL assembly;Plasma lipoprotein assembly;Chylomicron remodeling;Post-translational protein phosphorylation;HDL remodeling;ABC transporters in lipid homeostasis;Post-translational protein modification;Metabolism of proteins;HDL clearance;Metabolism;Plasma lipoprotein clearance;Transport of small molecules;Metabolism of vitamins and cofactors;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;ABC-family proteins mediated transport;Hemostasis;Plasma lipoprotein assembly, remodeling, and clearance;Retinoid metabolism and transport;G alpha (i) signalling events;Plasma lipoprotein remodeling;Visual phototransduction;Scavenging by Class B Receptors;Scavenging of heme from plasma;Binding and Uptake of Ligands by Scavenger Receptors;Scavenging by Class A Receptors;GPCR downstream signalling;FOXA2 and FOXA3 transcription factor networks (Consensus)

Intolerance Scores

• loftool: 0.397
• rvis_EVS: -0.47
• rvis_percentile_EVS: 23.04

Haploinsufficiency Scores

• pHI: 0.343
• hipred: N
• hipred_score: 0.461
• ghis: 0.905

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Apoa1
• Phenotype: liver/biliary 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); homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: retinoid metabolic process;regulation of protein phosphorylation;endothelial cell proliferation;platelet degranulation;negative regulation of cytokine secretion involved in immune response;phosphatidylcholine biosynthetic process;cholesterol biosynthetic process;receptor-mediated endocytosis;transforming growth factor beta receptor signaling pathway;G protein-coupled receptor signaling pathway;integrin-mediated signaling pathway;response to nutrient;cholesterol metabolic process;glucocorticoid metabolic process;negative regulation of tumor necrosis factor-mediated signaling pathway;positive regulation of cholesterol esterification;negative regulation of very-low-density lipoprotein particle remodeling;peripheral nervous system axon regeneration;protein oxidation;peptidyl-methionine modification;regulation of lipid metabolic process;triglyceride catabolic process;lipid storage;regulation of intestinal cholesterol absorption;cholesterol transport;adrenal gland development;animal organ regeneration;regulation of cholesterol transport;regulation of Cdc42 protein signal transduction;cholesterol efflux;phospholipid efflux;negative regulation of heterotypic cell-cell adhesion;chylomicron remodeling;very-low-density lipoprotein particle remodeling;high-density lipoprotein particle remodeling;chylomicron assembly;high-density lipoprotein particle assembly;high-density lipoprotein particle clearance;positive regulation of Rho protein signal transduction;lipoprotein metabolic process;lipoprotein biosynthetic process;response to drug;cholesterol homeostasis;blood vessel endothelial cell migration;response to estrogen;post-translational protein modification;reverse cholesterol transport;cellular protein metabolic process;positive regulation of lipid biosynthetic process;negative regulation of interleukin-1 beta secretion;negative regulation of inflammatory response;protein stabilization;negative chemotaxis;vitamin transport;positive regulation of hydrolase activity;positive regulation of stress fiber assembly;phospholipid homeostasis;negative regulation of lipase activity;negative regulation of cell adhesion molecule production;negative regulation of response to cytokine stimulus;triglyceride homeostasis;ERK1 and ERK2 cascade;cholesterol import;positive regulation of substrate adhesion-dependent cell spreading
• Cellular component: extracellular region;extracellular space;nucleus;early endosome;endoplasmic reticulum lumen;cytosol;plasma membrane;cell surface;endocytic vesicle;cytoplasmic vesicle;very-low-density lipoprotein particle;low-density lipoprotein particle;intermediate-density lipoprotein particle;high-density lipoprotein particle;discoidal high-density lipoprotein particle;spherical high-density lipoprotein particle;secretory granule lumen;chylomicron;collagen-containing extracellular matrix;extracellular exosome;endocytic vesicle lumen;blood microparticle;extracellular vesicle
• Molecular function: amyloid-beta binding;protein binding;phospholipid binding;phospholipid transporter activity;high-density lipoprotein particle binding;cholesterol binding;cholesterol transporter activity;enzyme binding;heat shock protein binding;apolipoprotein receptor binding;apolipoprotein A-I receptor binding;identical protein binding;chemorepellent activity;lipase inhibitor activity;phosphatidylcholine-sterol O-acyltransferase activator activity;high-density lipoprotein particle receptor binding