APOA4

protein-coding

apolipoprotein A4, the group of Apolipoproteins

Gene summary

Apoliprotein (apo) A-IV gene contains 3 exons separated by two introns. A sequence polymorphism has been identified in the 3'UTR of the third exon. The primary translation product is a 396-residue preprotein which after proteolytic processing is secreted its primary site of synthesis, the intestine, in association with chylomicron particles. Although its precise function is not known, apo A-IV is a potent activator of lecithin-cholesterol acyltransferase in vitro. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000482.4

Inheritance

ClinVar variants

P:2U:116B:51

Top phenotype

hereditary amyloidosis

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr11:116,820,700-116,823,304

External References & Databases

Ensembl (ENSG00000110244)

Transcript & Mutation Effects

hg38 • Region Span ~2.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary amyloidosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018634

Submitter: PanelApp Australia

autosomal dominant medullary cystic kidney disease with or without hyperuricemiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008264

Submitter: ClinGen

*APOA4* was first reported in relation to autosomal dominant tubulointerstitial kidney disease in 2023 (Kmochová et al., PMID: 38096951). Affected individuals develop chronic kidney disease with variable progression to end-stage kidney disease, with a mean age of end-stage kidney disease of approximately 60 years (range 45 to > 85). Urinalysis reveals a bland urinary sediment. Deep kidney biopsies or tissue obtained from nephrectomy reveal the deposition of medullary amyloidosis composed of the mutated *APOA4*. Two missense variants that have been reported in two probands in this publication (PMID: 38096951) are included in the curation. The mechanism of pathogenicity appears related to medullary deposition of the abnormal apolipoprotein. This gene-disease relationship is also supported by expression studies (PMID: 38096951). In summary, there is Limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Kidney Cystic and Ciliopathies Disorders GCEP on the meeting date February 28th, 2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to APOA4 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 132

not specifiedTotal: 56

APOA4-related disorderTotal: 10

Tubulointerstitial kidney disease, autosomal dominant 6Total: 2

APOLIPOPROTEIN A-IV RARE VARIANT, APOA4*0Total: 1

APOLIPOPROTEIN A-IV RARE VARIANT, APOA4*3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000482.4. 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				26 clinvar	7 clinvar	33
missense	2 clinvar		111 clinvar	14 clinvar	4 clinvar	131
nonsense			2 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	0	116	40	11	169

Highest pathogenic variant AF is 0.0000020525367

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000482.4	RefSeq	NP_000473.2	3	MANE Select
ENST00000357780.5	Ensembl	ENSP00000350425.3	3	MANE Select
ENST00001095766.1	Ensembl	ENSP00000765572.1	2	Standard
ENST00001095767.1	Ensembl	ENSP00000765573.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fat digestion and absorption - Homo sapiens (human)
Vitamin digestion and absorption - Homo sapiens (human)
Cholesterol metabolism - Homo sapiens (human)
Statin Pathway, Pharmacodynamics
Plasma lipoprotein assembly, remodeling, and clearance

Biological Process

retinoid metabolic process
innate immune response in mucosa
cholesterol biosynthetic process
lipid transport
response to lipid hydroperoxide

Molecular Function

lipid transporter activity
copper ion binding
protein binding
phospholipid binding
lipid binding

Cellular Component

extracellular region
extracellular space
early endosome
endoplasmic reticulum lumen
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357780
Coding exons: 3
Length: 2604
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.21	286	234	1.22	0.0000166	2581
Missense (PolyPhen)		59	50.834	1.1606		686
Synonymous	-0.729	116	106	1.09	0.00000788	786
Loss of Function	1.04	10	14.3	0.702	8.01e-7	146

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00051	0.00051	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have a role in chylomicrons and VLDL secretion and catabolism. Required for efficient activation of lipoprotein lipase by ApoC-II; potent activator of LCAT. Apoa-IV is a major component of HDL and chylomicrons.;

Recessive Scores

pRec: 0.0969

Intolerance Scores

LoFtool: 0.722
RVIS EVS: 0.36
RVIS percentile EVS: 74.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.834

Gene Damage Prediction

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