APOF

Summary

APOF (apolipoprotein F, HGNC:615) is a protein-coding gene on chromosome 12q13.3, encoding Apolipoprotein F (Q13790). Minor apolipoprotein that associates with LDL.

The product of this gene is one of the minor apolipoproteins found in plasma. This protein forms complexes with lipoproteins and may be involved in transport and/or esterification of cholesterol.

Source: NCBI Gene 319 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 45 total
• GTEx eGene: eQTL in 2 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.04 (LoF-tolerant), LOEUF 1.89 (unconstrained)
• MANE Select transcript: NM_001638

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:615
Approved symbol	APOF
Name	apolipoprotein F
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000175336
Ensembl biotype	protein_coding
OMIM	107760
Entrez	319

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000398189

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000398189, ENST00000887741, ENST00000887742, ENST00001121567, ENST00001121568, ENST00001139936

RefSeq mRNA: 1 — MANE Select: NM_001638 NM_001638

CCDS: CCDS44923

Canonical transcript exons

ENST00000398189 — 2 exons

Exon	Start	End
ENSE00001658798	56360568	56362189
ENSE00003512571	56362730	56362857

Expression profiles

Bgee: expression breadth broad, 32 present calls, max score 98.13.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9358 / max 564.1410, expressed in 14 samples.

Highest expression (Bgee): lobe of liver, liver, endometrium epithelium, granulocyte, frontal pole.

Genetic regulation across tissues (GTEx eQTL / sQTL)

APOF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 2 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

2 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Spinal cord cervical c-1	eqtl	1.5e-02	-0.76	12:56251102:A:G
Testis	eqtl	2.6e-02	+0.25	12:55479861:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
131521	0.8407	14
131522	0.0950	6

Top tissues by expression

showing 100 of 243 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.13	gold quality
liver	UBERON:0002107	96.47	gold quality
endometrium epithelium	UBERON:0004811	52.99	gold quality
granulocyte	CL:0000094	51.94	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
oviduct epithelium	UBERON:0004804	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
quadriceps femoris	UBERON:0001377	49.97	gold quality
thymus	UBERON:0002370	49.53	gold quality
vastus lateralis	UBERON:0001379	49.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
islet of Langerhans	UBERON:0000006	49.06	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
epithelial cell of pancreas	CL:0000083	48.61	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
oocyte	CL:0000023	47.74	gold quality
metanephric glomerulus	UBERON:0004736	47.74	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
buccal mucosa cell	CL:0002336	47.61	gold quality
renal glomerulus	UBERON:0000074	47.60	gold quality
layer of synovial tissue	UBERON:0007616	47.54	gold quality
kidney epithelium	UBERON:0004819	47.32	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
deltoid	UBERON:0001476	47.06	gold quality
diaphragm	UBERON:0001103	47.05	gold quality
gluteal muscle	UBERON:0002000	47.03	gold quality
triceps brachii	UBERON:0001509	47.01	gold quality
nephron tubule	UBERON:0001231	46.88	gold quality
bone marrow cell	CL:0002092	46.58	gold quality
metanephros	UBERON:0000081	45.40	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality
pancreatic ductal cell	CL:0002079	45.08	silver quality
muscle tissue	UBERON:0002385	44.37	gold quality
skeletal muscle tissue	UBERON:0001134	44.27	gold quality
prostate gland	UBERON:0002367	43.92	gold quality
trachea	UBERON:0003126	43.44	gold quality
squamous epithelium	UBERON:0006914	43.42	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
epithelium of esophagus	UBERON:0001976	42.87	gold quality
epithelium of bronchus	UBERON:0002031	42.75	gold quality
bronchus	UBERON:0002185	42.63	gold quality
bone marrow	UBERON:0002371	42.62	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
lower lobe of lung	UBERON:0008949	42.20	silver quality
cartilage tissue	UBERON:0002418	42.04	gold quality
kidney	UBERON:0002113	41.82	gold quality
medulla oblongata	UBERON:0001896	41.74	gold quality
blood	UBERON:0000178	41.64	gold quality
colonic epithelium	UBERON:0000397	41.51	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
epithelium of mammary gland	UBERON:0003244	41.33	gold quality
nasal cavity mucosa	UBERON:0001826	41.24	gold quality
dorsal plus ventral thalamus	UBERON:0001897	41.20	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
middle temporal gyrus	UBERON:0002771	41.07	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
upper leg skin	UBERON:0004262	40.96	silver quality
amniotic fluid	UBERON:0000173	40.69	gold quality
cranial nerve II	UBERON:0000941	40.65	silver quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
dorsal root ganglion	UBERON:0000044	40.51	gold quality
tibialis anterior	UBERON:0001385	40.48	silver quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
cortex of kidney	UBERON:0001225	40.41	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
caecum	UBERON:0001153	40.27	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
jejunum	UBERON:0002115	40.18	gold quality
tongue	UBERON:0001723	40.09	gold quality
mammary duct	UBERON:0001765	39.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	39.95	gold quality
pleura	UBERON:0000977	39.88	gold quality
saphenous vein	UBERON:0007318	39.83	gold quality
parotid gland	UBERON:0001831	39.81	gold quality
urethra	UBERON:0000057	39.80	gold quality
heart right ventricle	UBERON:0002080	39.79	gold quality
pericardium	UBERON:0002407	39.77	gold quality
pancreas	UBERON:0001264	39.76	gold quality
male germ cell	CL:0000015	39.75	gold quality
endothelial cell	CL:0000115	39.75	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enriched

40 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Liver	tissue	389.4
Medulla oblongata	tissue	2.7
Choroid plexus	tissue	2.4
Putamen	tissue	2.2
Locus coeruleus	tissue	2.1
Hippocampus	tissue	2.1
Postcentral gyrus	tissue	2.1
Retrosplenial cortex	tissue	2.1
Spinal cord	tissue	2.0
Nucleus accumbens	tissue	1.9
Substantia nigra	tissue	1.9
Prostate	tissue	1.1
Basal ganglia	tissue	0.6
Hypothalamus	tissue	0.6
Ventral forebrain	tissue	0.6
Olfactory bulb	tissue	0.6
Pons	tissue	0.5
Midbrain	tissue	0.5
Corpus callosum	tissue	0.5
Cerebral cortex	tissue	0.4
Entorhinal cortex	tissue	0.4
Retrosplenial and cingulate cortex	tissue	0.4
Retina	tissue	0.3
Frontal cortex	tissue	0.3
Amygdala	tissue	0.3
Testis	tissue	0.2
Cerebellum	tissue	0.2
Bone marrow	tissue	0.2
Somatosensory cortex	tissue	0.2
Occipital cortex	tissue	0.2
Lymph node	tissue	0.1
Breast	tissue	0.1
Salivary gland	tissue	0.1
Thalamus	tissue	0.1
Thyroid gland	tissue	0.1
Spleen	tissue	0.1
Kidney	tissue	0.1
Hippocampal formation	tissue	0.1
Septum	tissue	0.1
Appendix	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Parieto-temporal junction (white matter) (4.1), Flocculonodular lobe (3.5), Temporal white matter (3.4), Cerebellar cortex (3.3), Corpus callosum, genu (white matter) (3.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MIER1, NR1H4

miRNA regulators (miRDB)

Targeting APOF by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

15 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-655-5P	98.74	65.93	888
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-6822-3P	96.60	66.06	680
HSA-MIR-6879-3P	93.93	64.00	759

Functional genomics

gnomAD constraint: pLI 0.0351, LOEUF 1.89, missense Z 0.734 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000398189 — one region, missense o/e 0.95.

Literature-anchored findings (GeneRIF, showing 9)

• LTIP tailors CETP-mediated remodeling of HDL3 and HDL2 particles in subclass-specific ways, strongly implicating it as a regulator of HDL metabolism (PMID:12907677)
• we have confirmed the negative association between plasma triglyceride levels and Apolipoprotein F previously suggested by a small data set, but now we demonstrate that this effect is seen only in males. (PMID:17901467)
• lipoprotein composition may influence the status of lipid transfer inhibitor protein activity (PMID:18369235)
• LTIP translocation is dependent on LDL lipid composition (PMID:21937674)
• this study has identified apoF as likely another target gene of FXR. (PMID:24211198)
• Direct interactions between C/EBPalpha and ETS-1 were important for high liver-specific expression of ApoF. (PMID:25726912)
• Apolipoprotein F concentration, activity, and the properties of LDL controlling ApoF activation in hyperlipidemic plasma. (PMID:35016907)
• Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism. (PMID:35735979)
• A pan-cancer analysis of the oncogenic and immunological roles of apolipoprotein F (APOF) in human cancer. (PMID:37312170)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	apof	ENSDARG00000090980
mus_musculus	Apof	ENSMUSG00000047631
rattus_norvegicus	Apof	ENSRNOG00000062320

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:104539) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal coat/ hair morphology	1
increased circulating HDL cholesterol level	1
increased basophil cell number	1
decreased circulating triglyceride level	1
decreased cholesterol efflux	1
abnormal cholesterol homeostasis	1
increased liver cholesterol level	1

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIP	protein-coding	4284
TIMELESS	protein-coding	8914
IL23A	protein-coding	51561
STAT2	protein-coding	6773
PAN2	protein-coding	9924
CNPY2	protein-coding	10330
CNPY2-AS1	ncRNA	112268098

Protein

Protein identifiers

Apolipoprotein F — Q13790 (reviewed: Q13790)

Alternative names: Lipid transfer inhibitor protein

All UniProt accessions (1): Q13790

UniProt curated annotations — full annotation on UniProt →

Function. Minor apolipoprotein that associates with LDL. Inhibits cholesteryl ester transfer protein (CETP) activity and appears to be an important regulator of cholesterol transport. Also associates to a lesser degree with VLDL, Apo-AI and Apo-AII.

Subcellular location. Secreted.

Tissue specificity. Expressed by the liver and secreted in plasma.

Post-translational modifications. O-glycosylated with core 1 or possibly core 8 glycans.

Similarity. Belongs to the apolipoprotein F family.

RefSeq proteins (1): NP_001629* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026114	APOF	Family

Pfam: PF15148

UniProt features (7 total): glycosylation site 2, signal peptide 1, propeptide 1, chain 1, modified residue 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13790-F1	66.68	0.25

Human Protein Atlas

Protein class: Predicted secreted proteins, Plasma proteins

Protein evidence: Evidence at protein level

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1)

Type	Positions
Phosphoserine	323

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	118
O-linked (galnac…) threonine	274

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-8964041	LDL remodeling	curated
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance	—
R-HSA-8963899	Plasma lipoprotein remodeling	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 100 (showing top): GNF2_GSTM1, GNF2_HPN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_CHOLESTEROL_EFFLUX, GNF2_LCAT, HSIAO_LIVER_SPECIFIC_GENES, CAIRO_HEPATOBLASTOMA_DN, GOBP_LIPID_METABOLIC_PROCESS, GNF2_HPX, GOBP_NEUTRAL_LIPID_METABOLIC_PROCESS, GOBP_STEROL_TRANSPORT, GOMF_SIGNALING_RECEPTOR_BINDING

GO Biological Process (4): lipid metabolic process (GO:0006629), lipid transport (GO:0006869), cholesterol metabolic process (GO:0008203), steroid metabolic process (GO:0008202)

GO Molecular Function (4): signaling receptor binding (GO:0005102), lipid carrier activity (GO:0005319), cholesterol binding (GO:0015485), protein binding (GO:0005515)

GO Cellular Component (3): low-density lipoprotein particle (GO:0034362), high-density lipoprotein particle (GO:0034364), extracellular region (GO:0005576)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Plasma lipoprotein remodeling	1
Transport of small molecules	1
Plasma lipoprotein assembly, remodeling, and clearance	1

GO top-level categories

13 GO namespaces:

Category	Terms
plasma lipoprotein particle	2
primary metabolic process	1
transport	1
lipid localization	1
sterol metabolic process	1
secondary alcohol metabolic process	1
lipid metabolic process	1
protein binding	1
molecular carrier activity	1
sterol binding	1
alcohol binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

showing 15 of 718 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APOF	CETP	P11597	923
APOF	APOC4	P55056	630
APOF	APOA2	P02652	626
APOF	APOD	P05090	624
APOF	APOM	O95445	622
APOF	APOL1	O14791	621
APOF	PON1	P27169	591
APOF	APOH	P02749	585
APOF	APOC3	P02656	570
APOF	APOC2	P02655	570
APOF	APOC1	P02654	566
APOF	PLTP	P55058	566
APOF	APOA1	P02647	549
APOF	APOA4	P06727	549
APOF	CLU	P10909	514

IntAct

Human interaction partners of APOF in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
GALNT4	physical association	0.590	2
GAPDHS	physical association	0.400	1

BioGRID (6 interactions; top human partners by supporting records): GALNT4 (Affinity Capture-MS; 3 records), APOA1 (Co-purification), APOA2 (Co-purification), GAPDHS (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for APOF: 45 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

45 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	1
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 70):

Position(s)	Effect	Δscore	Sites
12:56362760	donor_gain	0.9200
12:56362190–56362191	acceptor_loss	0.7900	6
12:56362836	donor_gain	0.7800
12:56362192	acceptor_loss	0.7200
12:56362086	donor_gain	0.7000
12:56362727–56362729	donor_loss	0.6500	8
12:56362730	donor_loss	0.6400	2
12:56362730	donor_loss	0.6300
12:56362727	donor_loss	0.5800
12:56362726	donor_loss	0.5500

AlphaMissense

318 missense substitutions predicted likely pathogenic (of 2,085 scored), across 111 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D224	8	0.789	0.927
C206	7	0.958	0.974
C100	7	0.928	0.970
F76	7	0.927	0.987
C65	7	0.905	0.941
F85	7	0.901	0.976
C171	7	0.896	0.942
E176	7	0.866	0.904
D220	7	0.808	0.896
M79	6	0.634	0.641
K246	5	0.900	0.956
Y193	5	0.890	0.967
Y201	5	0.866	0.910
Y200	5	0.864	0.965
G217	5	0.854	0.934
T197	5	0.847	0.939
F192	5	0.816	0.856
P70	5	0.780	0.845
G252	5	0.730	0.842
P187	5	0.679	0.721

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Disease associations

OMIM: gene MIM:107760 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST006585_2428	Blood protein levels	7e-16
GCST002115_16	Axial length	4e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0005318	axial length measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects cotreatment, affects expression, decreases expression	2
lasiocarpine	decreases expression	1
bisphenol A	affects expression	1
chlortoluron	decreases expression	1
sodium arsenite	increases expression	1
tebuconazole	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Chlorpromazine	affects cotreatment, affects expression	1
Cholic Acids	affects cotreatment, affects expression	1
Niclosamide	decreases expression	1
Quercetin	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression, increases methylation	1
1-Naphthylisothiocyanate	affects cotreatment, affects expression	1
Aflatoxin B1	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.