AFP

Summary

AFP (alpha fetoprotein, HGNC:317) is a protein-coding gene on chromosome 4q13.3, encoding Alpha-fetoprotein (P02771). Binds copper, nickel, and fatty acids as well as, and bilirubin less well than, serum albumin.

This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. Alpha-fetoprotein expression in adults is often associated with hepatocarcinoma and with teratoma, and has prognostic value for managing advanced gastric cancer. However, hereditary persistance of alpha-fetoprotein may also be found in individuals with no obvious pathology. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin genes are present in tandem in the same transcriptional orientation on chromosome 4. Alpha-fetoprotein is found in monomeric as well as dimeric and trimeric forms, and binds copper, nickel, fatty acids and bilirubin. The level of alpha-fetoprotein in amniotic fluid is used to measure renal loss of protein to screen for spina bifida and anencephaly.

Source: NCBI Gene 174 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital deficiency in alpha-fetoprotein (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 113 total — 4 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 1 tissue, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 4
• Drug target: yes — 1 curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.96 (unconstrained)
• MANE Select transcript: NM_001134
• Interaction hub: 2,698 STRING partners (top 3% of genes corpus-wide)
• Notable: 113 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:317
Approved symbol	AFP
Name	alpha fetoprotein
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	FETA
Ensembl gene	ENSG00000081051
Ensembl biotype	protein_coding
OMIM	104150
Entrez	174

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

MANE Select: ENST00000395792

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 5: 1

ENST00000395792, ENST00000226359, ENST00000506820, ENST00000508838, ENST00000513720, ENST00000514279, ENST00000515675, ENST00001100731, ENST00001100732

RefSeq mRNA: 2 — MANE Select: NM_001134 NM_001134, NM_001354717

CCDS: CCDS3556

Canonical transcript exons

ENST00000395792 — 15 exons

Exon	Start	End
ENSE00000721660	73438174	73438306
ENSE00000721666	73440602	73440813
ENSE00000721670	73442296	73442428
ENSE00000721710	73443347	73443444
ENSE00000721712	73444993	73445122
ENSE00000721715	73447462	73447676
ENSE00000721718	73449335	73449467
ENSE00000721757	73450036	73450133
ENSE00000721759	73450615	73450753
ENSE00000904413	73437160	73437211
ENSE00001522871	73436221	73436347
ENSE00002061556	73455631	73456174
ENSE00003577901	73455236	73455290
ENSE00003619455	73453765	73453897
ENSE00003644733	73452401	73452624

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 82.17.

FANTOM5 (CAGE): breadth broad, TPM avg 85.2228 / max 11239.7707, expressed in 230 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, lobe of liver, adrenal tissue, liver.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AFP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 1 tissue and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

1 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Liver	eqtl	2.2e-31	-0.59	4:73410104:A:T

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
48142	84.8321	144
48149	0.1678	108
203215	0.1010	39
203214	0.0878	30
48150	0.0341	17

Top tissues by expression

showing 100 of 279 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.17	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.88	gold quality
right lobe of liver	UBERON:0001114	81.87	gold quality
adrenal tissue	UBERON:0018303	80.95	gold quality
liver	UBERON:0002107	73.54	gold quality
adult mammalian kidney	UBERON:0000082	66.55	gold quality
embryo	UBERON:0000922	61.39	gold quality
kidney	UBERON:0002113	60.31	gold quality
amniotic fluid	UBERON:0000173	59.83	silver quality
metanephros	UBERON:0000081	59.13	gold quality
mammary duct	UBERON:0001765	58.70	silver quality
buccal mucosa cell	CL:0002336	56.95	gold quality
right adrenal gland cortex	UBERON:0035827	56.16	gold quality
pancreatic ductal cell	CL:0002079	55.66	silver quality
cranial nerve II	UBERON:0000941	54.54	silver quality
ascending aorta	UBERON:0001496	53.10	gold quality
thoracic aorta	UBERON:0001515	52.95	gold quality
metanephros cortex	UBERON:0010533	52.62	gold quality
thoracic mammary gland	UBERON:0005200	52.48	gold quality
mammary gland	UBERON:0001911	52.40	gold quality
cortex of kidney	UBERON:0001225	51.54	gold quality
prefrontal cortex	UBERON:0000451	51.27	gold quality
Brodmann (1909) area 46	UBERON:0006483	50.99	gold quality
epithelial cell of pancreas	CL:0000083	50.44	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
right adrenal gland	UBERON:0001233	50.22	gold quality
quadriceps femoris	UBERON:0001377	50.18	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
thymus	UBERON:0002370	49.51	gold quality
vastus lateralis	UBERON:0001379	49.45	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
Brodmann (1909) area 9	UBERON:0013540	48.99	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
oviduct epithelium	UBERON:0004804	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
deltoid	UBERON:0001476	48.39	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	48.30	gold quality
left uterine tube	UBERON:0001303	48.29	gold quality
middle temporal gyrus	UBERON:0002771	48.29	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
nephron tubule	UBERON:0001231	47.89	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
metanephric glomerulus	UBERON:0004736	47.74	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
kidney epithelium	UBERON:0004819	47.66	gold quality
renal glomerulus	UBERON:0000074	47.60	gold quality
layer of synovial tissue	UBERON:0007616	47.54	gold quality
primary visual cortex	UBERON:0002436	47.44	gold quality
adrenal gland	UBERON:0002369	47.41	gold quality
frontal cortex	UBERON:0001870	47.33	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
inferior olivary complex	UBERON:0002127	47.07	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
endometrium epithelium	UBERON:0004811	46.85	gold quality
smooth muscle tissue	UBERON:0001135	46.55	gold quality
myometrium	UBERON:0001296	46.32	gold quality
descending thoracic aorta	UBERON:0002345	46.12	gold quality
muscle tissue	UBERON:0002385	46.04	gold quality
adult organism	UBERON:0007023	46.04	gold quality
fallopian tube	UBERON:0003889	45.94	gold quality
occipital lobe	UBERON:0002021	45.84	gold quality
neocortex	UBERON:0001950	45.79	gold quality
cerebral cortex	UBERON:0000956	45.51	gold quality
tibialis anterior	UBERON:0001385	45.50	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
ovary	UBERON:0000992	45.28	gold quality
rectum	UBERON:0001052	44.88	gold quality
skeletal muscle tissue	UBERON:0001134	44.44	gold quality
left ovary	UBERON:0002119	44.04	gold quality
cardiac atrium	UBERON:0002081	43.96	gold quality
adrenal cortex	UBERON:0001235	43.85	gold quality
squamous epithelium	UBERON:0006914	43.83	gold quality
left adrenal gland	UBERON:0001234	43.74	gold quality
right frontal lobe	UBERON:0002810	43.56	gold quality
epithelium of esophagus	UBERON:0001976	43.45	gold quality
trachea	UBERON:0003126	43.44	gold quality
right atrium auricular region	UBERON:0006631	43.38	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
cartilage tissue	UBERON:0002418	43.16	gold quality
Ammon’s horn	UBERON:0001954	42.94	gold quality
epithelium of bronchus	UBERON:0002031	42.78	gold quality
bronchus	UBERON:0002185	42.66	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
superior frontal gyrus	UBERON:0002661	42.38	silver quality
islet of Langerhans	UBERON:0000006	42.37	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	33922.41
E-GEOD-130473	yes	29492.33
E-MTAB-6701	yes	20482.66
E-MTAB-9388	yes	18362.90
E-HCAD-10	yes	1631.54
E-ANND-5	yes	936.96
E-ANND-3	yes	4.04

HPA expression

RNA tissue specificity: Tissue enriched

8 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	3.4	not detected
Breast	tissue	0.3	not detected
Epididymis	tissue	0.2	not detected
Spinal cord	tissue	0.2
Caudate putamen	tissue	0.2
Ovary	tissue	0.1	not detected
Medulla oblongata	tissue	0.1
Hypothalamus	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 4; highest nTPM — Dorsal spinal cord (0.2), Angular gyrus (white matter) (0.1), Area parastriata, inferior (0.1), Area striata (0.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CBX1, CEBPA, CEBPB, CEBPG, DBP, FOS, FOXA1, FOXA2, FOXC1, FOXM1, FOXN1, HIF1A, HNF1A, HNF1B, HNF4A, HNF4G, ING1, ING2, JUN, LHX4, MYC, NANOG, NF1, NFIC, NKX2-1, NKX2-8, NR1D1, NR1D2, NR3C1, NR5A1, NR5A2, ONECUT1, PDX1, POU5F1, RARB, RORA, SIRT2, SKIL, TBP

miRNA regulators (miRDB)

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

20 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-1270	96.94	66.65	931
HSA-MIR-620	96.94	66.79	888
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-217-3P	95.67	68.42	1000

Functional genomics

gnomAD constraint: pLI 5.23e-14, LOEUF 0.963, missense Z 0.672 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000395792 — one region, missense o/e 0.98.

Literature-anchored findings (GeneRIF, showing 40)

• blood levels of the neoplasm protein can be used to monitor hepatoblastoma response to therapy and modify treatment (PMID:11764100)
• both the ratio of AFP-L3 (AFP-L3%) and the absolute value of AFP-L3 (AFP-L3-AV) were examined in 80 patients with HCC, and evaluated with respect to characteristics of HCC such as grade of differentiation, size of tumor and morphological findings (PMID:11788893)
• Repression of alpha-fetoprotein gene expression under hypoxic conditions in human hepatoma cells: characterization of a negative hypoxia response element that mediates opposite effects of hypoxia inducible factor-1 and c-Myc. (PMID:11861398)
• Variant forms of transcripts expressed in human hematopoietic progenitors; Implications for their developmental potential towards endoderm (PMID:12006569)
• Nkx2.8 bound to the active AFP promoter, and antisense inhibition of Nkx2.8 mRNA translation selectively reduced expression of both the endogenous human AFP gene and transfected reporters containing the rat AFP promoter. (PMID:12167706)
• alpha-fetoprotein directly binds to CCR5 in primary macrophages (PMID:12176010)
• The alpha-fetoprotein gene is expressed in cytotrophoblasts from early human placentas. (PMID:12361680)
• APF is fucosylated in hepatoma cells after treatment with acyclic retinoid (PMID:12499776)
• alpha-fetoprotein regulates neoplastic growth through the presence of an alpha-fetoprotein cell surface receptor (review) (PMID:12503217)
• Degree of alterations in maternal serum hCG and alpha-fetoprotein levels varied between fresh and frozen-thawed embryos and also between mode of fertilization. (PMID:12615827)
• positively regulates cytochrome c/dATP-mediated apoptosome complex formation (PMID:14622304)
• AFP is a diagnostic but rather insensitive tissue marker for hepatocellular carcinoma (PMID:14714299)
• AFP may act as a specific proangiogenic factor of endothelial cells within the fetomaternal unit during advanced stages in pregnancy (PMID:15001643)
• mouse and human alpha-fetoprotein enhancers are strikingly different (PMID:15028291)
• AFP can stimulate the expression of some oncogenes to enhance the proliferation of human hepatocellular carcinoma Bel 7402 cells. (PMID:15040024)
• AFP induces dysfunction and apoptosis of APCs, offering a mechanism by which hepatocellular carcinoma escapes immunological control. (PMID:15265907)
• This first identification of a mutation in the AFP gene demonstrates for the first time that deficiency of AFP is compatible with human normal fetal development and further reproduction in males. (PMID:15280901)
• AFP elevation appears to contribute to vascular invasion and hepatocellular carcinoma progression (PMID:15305374)
• AFP is able to promote the expression of FasL and TRAIL in hepatoma cells and enhance the expression of Fas and TRAILR in lymphocytes (PMID:15849812)
• alpha-FP and SCCA yielded a correct serologic diagnosis in 90.83% of the hepatocarcinoma patients. (PMID:15906357)
• AFP mRNA is a more reliable marker of metastasis compared to serum AFP (PMID:15993394)
• Transient co-transfection of p53 family members showed that p53 and transactivating (TA)-p73, but not TA-p63, repress endogenous AFP transcription additively or independently. (PMID:16203738)
• The gene expression profile of hepatoblasts throughout life consists of high levels of expression of alpha-fetoprotein(AFP). (PMID:16627685)
• We show here that alpha-fetoprotein cancels XIAP-mediated inhibition of endogenous active caspases in cytosolic lysates of tumor cells, as well as XIAP-induced blockage of active recombinant caspase 3 in a reconstituted cell-free system. (PMID:16869888)
• We demonstrated that foldability of the AFP molecule from its denatured-reduced state is independent of its starting source, the presence or absence of glycosylation and fatty acids, and the refolding method used (dialysis or dilution). (PMID:16882993)
• mRNA may be a predictive value for recurrence of hepatocellular carcinoma in living donor liver transplantation. (PMID:17175353)
• AFP mRNA-expressing cells may be a useful predictor of hepatocellular carcinoma recurrence in liver transplant patients. (PMID:17175354)
• These results indicate that C/EBPalpha regulates AFP gene expression through direct binding to multiple sites in the human AFP gene in cultured human cells. (PMID:17188819)
• describe the case of a 44-year-old woman who presented with vaginal bleeding, pelvic mass, and preoperative elevated AFP serum level (PMID:17197899)
• effects of a necrosis-inducing treatment (embolization) on anti-alpha-fetoprotein (AFP)-specific CD4(+) T cell responses in hepatocellular carcinoma (HCC) patients and controls using an array of AFP-derived peptides. (PMID:17237442)
• The positive rate of AFP mRNA in liver transplantation patients is higher than that at preoperation, a difference that is statistically significant (PMID:17275497)
• The novel polymorphisms identified in the promoter region of the AFP gene may be pathologically significant in HCC. (PMID:17433605)
• AFP increase in patients with liver cancer was positively correlated with the infection of HBV and HCV. The serum AFP elevation by the infection of HBV and HCV is one of mechanisms which lead to hepatocarcinogenesis (PMID:17465484)
• Mesenchymal hamartoma of the liver reported with features of Beckwith-Wiedemann syndrome and high AFP levels. (PMID:17535089)
• Serum AFP levels ranging between 200-800 ng/ml were associated with high expression of somatostatin receptors in hepatocellular carcinoma. (PMID:17626741)
• Higher baseline serum AFP levels independently predicted a lower sustained viral response to antivirals among patients with chronic hepatitis C. (PMID:17713163)
• Results show that measurements of AFP, CEA and CA125 are more readily affected by long-term frozen storage compared with frequent freezing-thawing. (PMID:17852813)
• The presence of AFP mRNA in preoperative peripheral blood is related to tumor invasion of hepatocellular carcinoma. (PMID:18184471)
• These data support the idea that ZHX2 contributes to AFP repression in the liver after birth and may also be involved in AFP reactivation in liver cancer. (PMID:18194454)
• EpCAM and alpha-fetoprotein are expressed in hepatocellular carcinoma (PMID:18316609)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Afp	ENSMUSG00000054932
rattus_norvegicus	Afp	ENSRNOG00000002889

Paralogs (3): AFM (ENSG00000079557), GC (ENSG00000145321), ALB (ENSG00000163631)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:87951) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal ovary morphology	1
absent corpus luteum	1
increased circulating follicle stimulating hormone level	1
increased circulating luteinizing hormone level	1
female infertility	1
abnormal sexual interaction	1
decreased circulating progesterone level	1
anovulation	1
absent estrous cycle	1
endometrium hyperplasia	1
failure of copulatory plug deposition	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	A2V9Z4	100.0%	Diamond
Macaca mulatta	Q28522	100.0%	Diamond
Gorilla gorilla gorilla	P28050	99.3%	Diamond
Pan troglodytes	Q28789	99.0%	Diamond
Equus caballus	P35747	98.5%	Diamond
Pongo abelii	Q5NVH5	98.5%	Diamond
Equus asinus	Q5XLE4	98.5%	Diamond
Bos taurus	P02769	91.8%	Diamond
Ovis aries	P14639	91.8%	Diamond
Xenopus laevis	P08759	89.3%	Diamond
Sus scrofa	Q8MJ76	89.3%	Diamond
Canis lupus familiaris	Q8MJU5	89.3%	Diamond
Felis catus	P49064	87.0%	Diamond
Mesocricetus auratus	A6YF56	84.4%	Diamond
Meriones unguiculatus	O35090	82.6%	Diamond
Oryctolagus cuniculus	P49065	76.1%	Diamond
Gallus gallus	P19121	73.5%	Diamond
Bombina maxima	Q3T478	48.2%	Diamond
Aquarana catesbeiana	P21847	44.5%	Diamond
Neoceratodus forsteri	P83517	42.0%	Diamond

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
ANKRD17-AS1	ncRNA	124900713
ALB	protein-coding	213
ANKRD17	protein-coding	26057
ANKRD17-DT	ncRNA	102724832
AFM	protein-coding	173
LINC02499	ncRNA	728040

Protein

Protein identifiers

Alpha-fetoprotein — P02771 (reviewed: P02771)

Alternative names: Alpha-1-fetoprotein, Alpha-fetoglobulin

All UniProt accessions (2): P02771, J3KMX3

UniProt curated annotations — full annotation on UniProt →

Function. Binds copper, nickel, and fatty acids as well as, and bilirubin less well than, serum albumin. Only a small percentage (less than 2%) of the human AFP shows estrogen-binding properties.

Subunit / interactions. Dimeric and trimeric forms have been found in addition to the monomeric form.

Subcellular location. Secreted.

Tissue specificity. Plasma. Synthesized by the fetal liver and yolk sac.

Post-translational modifications. Independent studies suggest heterogeneity of the N-terminal sequence of the mature protein and of the cleavage site of the signal sequence. Sulfated.

Disease relevance. Alpha-fetoprotein deficiency (AFPD) [MIM:615969] A benign condition characterized by undetectable AFP levels in the amniotic fluid. Affected individuals are asymptomatic and present normal development. The disease is caused by variants affecting the gene represented in this entry. Alpha-fetoprotein, hereditary persistence (HPAFP) [MIM:615970] A benign autosomal dominant condition characterized by continued expression of alpha-fetoprotein in adult life. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ALB/AFP/VDB family.

RefSeq proteins (2): NP_001125, NP_001341646 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000264	ALB/AFP/VDB	Family
IPR014760	Serum_albumin_N	Domain
IPR020857	Serum_albumin_CS	Conserved_site
IPR020858	Serum_albumin-like	Homologous_superfamily
IPR021177	Serum_albumin/AFP/Afamin	Family

Pfam: PF00273

UniProt features (74 total): helix 35, disulfide bond 15, modified residue 6, strand 5, turn 4, domain 3, sequence variant 2, signal peptide 1, chain 1, glycosylation site 1, binding site 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
3MRK	Crystal Structure of MHC class I HLA-A2 molecule complexed with AFP137 nonapeptide	X-RAY DIFFRACTION	1.4
7RE7	TCR mimic antibody (Fab fragment) in complex with AFP/HLA-A*02	X-RAY DIFFRACTION	2.55
7YIM	Cryo-EM structure of human Alpha-fetoprotein	ELECTRON MICROSCOPY	2.6
7RE8	Class I MHC (HLA-A*02) presenting alpha fetoprotein peptide (AFP)	X-RAY DIFFRACTION	2.82
8X1N	Cryo-EM structure of human alpha-fetoprotein	ELECTRON MICROSCOPY	3.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02771-F1	88.83	0.75

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 7RE7

Human Protein Atlas

Protein class: Predicted secreted proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

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

Ligand- & substrate-binding residues (1)

Position	Role
22	Cu(2+)

Post-translational modifications (6)

Type	Positions
Phosphoserine	444, 445, 111, 115, 117, 344

Disulfide bonds (15)

Type	Positions
Disulfide bond	99–114, 113–124, 148–193, 192–201, 224–270, 269–277, 289–303, 302–313, 384–393, 416–462, 461–472, 485–501, 500–511, 538–583, 582–591

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	251

Function

Pathways and Gene Ontology

Reactome pathways

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

4 pathways:

ID	Pathway	Evidence
R-HSA-8957275	Post-translational protein phosphorylation	curated
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	curated
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 220 (showing top): PID_HNF3B_PATHWAY, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, CERVERA_SDHB_TARGETS_1_DN, HNF1_Q6, PID_REG_GR_PATHWAY, GOBP_KETONE_METABOLIC_PROCESS, PATIL_LIVER_CANCER, chr4q13, CDP_01, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM3, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GOBP_OVULATION_CYCLE_PROCESS, GOBP_OVULATION, HESS_TARGETS_OF_HOXA9_AND_MEIS1_UP

GO Biological Process (1): response to nutrient levels (GO:0031667)

GO Molecular Function (3): small molecule binding (GO:0036094), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (3): endoplasmic reticulum lumen (GO:0005788), extracellular region (GO:0005576), cytoplasm (GO:0005737)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Metabolism of proteins	2
Post-translational protein modification	1

GO top-level categories

7 GO namespaces:

Category	Terms
binding	2
cellular anatomical structure	2
response to stimulus	1
cation binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

showing 15 of 2,698 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFP	CEACAM5	P06731	921
AFP	F2	P00734	883
AFP	GPT	P24298	882
AFP	GPC3	P51654	859
AFP	KRT19	P08727	837
AFP	ZBTB20	Q9HC78	781
AFP	FOXA2	Q9Y261	780
AFP	ZHX2	Q9Y6X8	767
AFP	KLK3	P07288	752
AFP	TTR	P02766	741
AFP	FAH	P16930	731
AFP	KRT7	P08729	720
AFP	SETX	Q7Z333	719
AFP	GPT2	Q8TD30	719
AFP	PAPPA	Q13219	718

IntAct

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

11 partners by confidence:

Partner	Interaction type	MIscore	Records
GPC3	direct interaction	0.590	2
AP4S1	physical association	0.370	1
EHD4	physical association	0.370	1
GNB1	physical association	0.370	1
MED27	physical association	0.370	1
PHB2	physical association	0.370	1
PIDD1	physical association	0.370	1
PSMB7	physical association	0.370	1
DCUN1D4	association	0.350	1
HLA-B	physical association	0.000	1
SGSM2	physical association	0.000	1

BioGRID (37 interactions; top human partners by supporting records): CREBBP (Biochemical Activity; 4 records), SIRT1 (Affinity Capture-Western; 3 records), CASP3 (Affinity Capture-Western; 2 records), PTEN (Affinity Capture-Western; 2 records), XIAP (Affinity Capture-Western; 2 records), AP4S1 (Two-hybrid), ASXL1 (Affinity Capture-MS), C9orf72 (Affinity Capture-MS), CCR5 (Affinity Capture-Western), DCUN1D4 (Affinity Capture-MS), EHD4 (Two-hybrid), FBXW10 (Affinity Capture-MS), FIS1 (Affinity Capture-MS), GNB1 (Two-hybrid), HDLBP (Affinity Capture-MS)

SIGNOR signaling

showing 13 of 16 signaling interactions:

A	Effect	B	Mechanism
HNF1A	“up-regulates quantity by expression”	AFP	“transcriptional regulation”
ZFHX3	“down-regulates quantity by repression”	AFP	“transcriptional regulation”
HNF4G	“up-regulates quantity by expression”	AFP	“transcriptional regulation”
“all-trans-retinoic acid”	“down-regulates quantity by repression”	AFP
HNF4A	“up-regulates quantity by expression”	AFP	“transcriptional regulation”
ING1	“down-regulates quantity by repression”	AFP	“transcriptional regulation”
TP53	“down-regulates quantity by repression”	AFP	“transcriptional regulation”
ING2	“down-regulates quantity by repression”	AFP	“transcriptional regulation”
SIRT2	“up-regulates quantity by expression”	AFP	“transcriptional regulation”
NANOG	“down-regulates quantity by repression”	AFP	“transcriptional regulation”
NF1	“down-regulates quantity by repression”	AFP	“transcriptional regulation”
HNF1B	“up-regulates quantity by expression”	AFP	“transcriptional regulation”
ZBTB20	“down-regulates quantity by repression”	AFP	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for AFP: 113 ClinVar records (5 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	79
Likely benign	18
Benign	7

Top pathogenic / likely-pathogenic (5)

Showing all 5 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
929747	NM_001134.3(AFP):c.1822G>A (p.Gly608Arg)	Likely pathogenic	criteria provided, single submitter	1
18168	NC_000004.12:g.73436100G>A	Pathogenic	criteria provided, single submitter	2
1684642	NC_000004.12:g.67833055_82716065del	Pathogenic	criteria provided, single submitter	1
18169	NM_001134.3(AFP):c.883_884del (p.Leu295fs)	Pathogenic	no assertion criteria provided	1
18170	NM_001134.3(AFP):c.543G>A (p.Trp181Ter)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore AFP’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 1,034):

Position(s)	Effect	Δscore	Sites
4:73438307	donor_loss	1.0000	2
4:73443345–73443346	acceptor_loss	1.0000	5
4:73443445–73443446	donor_loss	1.0000	5
4:73449327–73449329	acceptor_gain	1.0000	2
4:73449460	donor_gain	1.0000
4:73449468–73449469	donor_loss	1.0000	5
4:73450034–73450035	acceptor_loss	1.0000	5
4:73450113	donor_gain	1.0000
4:73450130	donor_gain	1.0000
4:73450754–73450755	donor_loss	1.0000	5

AlphaMissense

576 missense substitutions predicted likely pathogenic (of 4,020 scored), across 175 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
C501	7	0.942	0.973
C485	7	0.934	0.961
C270	7	0.926	0.960
C277	7	0.919	0.958
C500	7	0.919	0.959
C416	7	0.911	0.945
C313	7	0.910	0.960
C224	7	0.904	0.946
C289	7	0.904	0.946
C511	7	0.903	0.936
C303	7	0.902	0.946
C461	7	0.900	0.939
C269	7	0.898	0.945
C462	7	0.893	0.932
C472	7	0.884	0.925
C302	7	0.876	0.936
C538	7	0.865	0.930
C99	7	0.860	0.923
C148	7	0.856	0.917
C582	7	0.826	0.908

HPA cancer prognostics

RNA cancer specificity: Group enriched (Liver Hepatocellular Carcinoma, Testicular Germ Cell Tumor)

Disease associations

OMIM: gene MIM:104150 | disease phenotypes:

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
congenital deficiency in alpha-fetoprotein	Moderate	Autosomal recessive	2
hereditary persistence of alpha-fetoprotein	Moderate	Autosomal dominant	2

Mondo (3): primary ovarian failure (MONDO:0005387), (MONDO:0014424), (MONDO:0014425)

Orphanet (3): Hereditary persistence of alpha-fetoprotein (Orphanet:168615), Congenital deficiency in alpha-fetoprotein (Orphanet:168612), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

4 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0006254	Elevated circulating alpha-fetoprotein concentration
HP:0045057	Decreased circulating alpha-fetoprotein concentration

GWAS associations

3 associations:

Study	Trait	p-value
GCST001808_10	Tumor biomarkers	3e-18
GCST001942_8	Prostate cancer	5e-13
GCST006585_1037	Blood protein levels	2e-9

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0005127	cancer biomarker measurement

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C566300	alpha-Fetoprotein Deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712864 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the AFP protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
YTTRIUM Y 90 TACATUZUMAB TETRAXETAN	Antibody	2

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

79 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	4
Cyclosporine	decreases expression, increases expression	4
sodium arsenite	decreases reaction, increases expression, decreases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
methylmercuric chloride	decreases expression	2
bisphenol A	affects expression, increases expression, affects reaction	2
perfluorooctanoic acid	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Chir 99021	affects binding, increases expression, affects cotreatment, decreases expression	2
Arsenic Trioxide	decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
Tretinoin	affects expression, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation, increases expression	2
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
deoxynivalenol	decreases expression	1
decabromobiphenyl ether	increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
zinc chloride	decreases expression	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	increases expression	1
nivalenol	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, decreases expression	1
mercuric bromide	affects cotreatment, increases expression	1
diethylstilbestrol monophosphate	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8B2	Abcam HCT 116 AFP KO	Cancer cell line	Male
CVCL_B9D4	Abcam A-549 AFP KO	Cancer cell line	Male
CVCL_D2DU	Abcam MCF-7 AFP KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

showing 60 of 75 trials:

NCT	Phase	Status	Title
NCT00417066	Phase 4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	Phase 4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	Phase 4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	Phase 4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	Phase 4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	Phase 4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	Phase 3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	Phase 2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	Phase 2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	Phase 2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	Phase 2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	Phase 2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	Phase 2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	Phase 1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	Phase 1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	Phase 1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	Phase 1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	Phase 1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	Phase 2/3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	Phase 2/3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	Phase 1/2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	Phase 1/2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	Phase 1/2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	Phase 1/2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	Phase 1/2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	Phase 1/2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	Phase 1/2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	Phase 1/2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	Phase 1/2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	Phase 1/2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	Phase 1/2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	Phase 1/2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	Phase 1/2	COMPLETED	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	Early Phase 1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	Early Phase 1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	Early Phase 1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists
NCT00295087	Not specified	COMPLETED	X-Chromosome Inactivation Status and Premature Ovarian Failure
NCT00417157	Not specified	COMPLETED	Modified Natural Cycle Offers a Chance of Pregnancy in Patients With Poor Response and High Basal FSH
NCT00619333	Not specified	UNKNOWN	Inactive FSH in Galactosemia
NCT00780897	Not specified	UNKNOWN	Premature Ovarian Failure (Genetic and Physiopathologic Analysis)
NCT01187524	Not specified	TERMINATED	The Natural History of Reproductive and Overall Health in Girls and Women With a Pre-Mutation in the FMR1 Gene; Creation of a Patient Registry
NCT01411644	Not specified	UNKNOWN	Pheno- & Genotyping POF (WHO III)
NCT02086318	Not specified	UNKNOWN	A New Algorithm to Predict Ovarian Age
NCT02467231	Not specified	ACTIVE_NOT_RECRUITING	Ovarian Reserve After Cancer: Longitudinal Effects
NCT02696889	Not specified	COMPLETED	Rejuvenation of Premature Ovarian Failure With Stem Cells
NCT02779374	Not specified	TERMINATED	Autologous Bone Marrow Transplantation for Premature Ovarian Insufficiency
NCT03207412	Not specified	UNKNOWN	Human Amniotic Epithelial Cells Treatment for Ovarian Insufficiency
NCT03381300	Not specified	ACTIVE_NOT_RECRUITING	Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome
NCT03412487	Not specified	UNKNOWN	Ovarian Histopathology and Laparoscopic Assessment of Premature Ovarian Failure
NCT03474120	Not specified	UNKNOWN	Prospective Genetic Study in Patients With Ovarian Insufficiency
NCT03480412	Not specified	UNKNOWN	Second Step Protocol in Poor Ovarian Responder (POR)
NCT03840824	Not specified	COMPLETED	Blood Spot Self-administered Test and Assay
NCT03861715	Not specified	UNKNOWN	Single Follicular Dexarelix for LH Suppression During Ovarian Stimulation in Oocyte Donors.
NCT03924648	Not specified	COMPLETED	Endocan Levels in Women With Premature Ovarian Insufficiency
NCT04149028	Not specified	COMPLETED	Platelet Rich Plasma Injection Into Ovary of Patients With Premature Ovarian Insufficiency
NCT04189406	Not specified	UNKNOWN	Turner Syndrome Minipuberty Study