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): 106 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_001134

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: 7 — 3 protein_coding_CDS_not_defined, 2 protein_coding, 2 retained_intron

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

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.

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

279 total, 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

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

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)

20 targeting AFP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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)

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 (67 total): helix 28, 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.

PDB	Method	Resolution (Å)
3MRK	X-RAY DIFFRACTION	1.4
7RE7	X-RAY DIFFRACTION	2.55
7YIM	ELECTRON MICROSCOPY	2.6
7RE8	X-RAY DIFFRACTION	2.82
8X1N	ELECTRON MICROSCOPY	3.31

Predicted structure (AlphaFold)

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

Antibody-complex structures (SAbDab): 1 — 7RE7

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): 22

Post-translational modifications (6): 444, 445, 111, 115, 117, 344

Disulfide bonds (15): 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): 251

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation

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 (6): ovulation from ovarian follicle (GO:0001542), apoptotic process (GO:0006915), immune response (GO:0006955), response to nutrient levels (GO:0031667), progesterone metabolic process (GO:0042448), homeostasis of number of cells (GO:0048872)

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

GO Cellular Component (4): obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular region (GO:0005576), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stimulus	2
binding	2
cellular anatomical structure	2
female gonad development	1
ovulation cycle process	1
ovulation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
immune system process	1
C21-steroid hormone metabolic process	1
ketone metabolic process	1
olefinic compound metabolic process	1
multicellular organismal-level homeostasis	1
cation binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFP	CEACAM5	P06731	941
AFP	F2	P00734	929
AFP	SERPINA1	P01009	907
AFP	GPT	P24298	895
AFP	GPC3	P51654	871
AFP	KRT19	P08727	851
AFP	ALB	P02768	848
AFP	TTR	P02766	845
AFP	FOXA2	Q9Y261	781
AFP	ZHX2	Q9Y6X8	774
AFP	FAH	P16930	774
AFP	ZBTB20	Q9HC78	774
AFP	KLK3	P07288	767
AFP	GPT2	Q8TD30	748
AFP	INS	P01308	744

IntAct

22 interactions, top by confidence:

A	B	Type	Score
STAMBP	PIK3C2A	psi-mi:“MI:0914”(association)	0.730
AFP	GPC3	psi-mi:“MI:0407”(direct interaction)	0.590
AFP	GPC3	psi-mi:“MI:0915”(physical association)	0.590
	AFP	psi-mi:“MI:0915”(physical association)	0.500
AFP	GNB1	psi-mi:“MI:0915”(physical association)	0.370
PSMB7	AFP	psi-mi:“MI:0915”(physical association)	0.370
AFP	MED27	psi-mi:“MI:0915”(physical association)	0.370
AFP	AP4S1	psi-mi:“MI:0915”(physical association)	0.370
AFP	PHB2	psi-mi:“MI:0915”(physical association)	0.370
AFP	EHD4	psi-mi:“MI:0915”(physical association)	0.370
PIDD1	AFP	psi-mi:“MI:0915”(physical association)	0.370
		psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
DCUN1D4	AFP	psi-mi:“MI:0914”(association)	0.350
FGG	ACOT7	psi-mi:“MI:0914”(association)	0.350
KIAA1191	UBA6	psi-mi:“MI:0914”(association)	0.350
GPC3	PXDNL	psi-mi:“MI:0914”(association)	0.350
HLA-B	AFP	psi-mi:“MI:0915”(physical association)	0.000
SGSM2	AFP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (33): AFP (Two-hybrid), AFP (Two-hybrid), CCR5 (Affinity Capture-Western), AFP (Biochemical Activity), CREBBP (Affinity Capture-Western), AFP (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), AFP (Affinity Capture-Western), CREBBP (Reconstituted Complex), SIRT1 (Reconstituted Complex), PTEN (Affinity Capture-Western), PTEN (Reconstituted Complex), CASP3 (Affinity Capture-Western), CASP3 (Reconstituted Complex), AFP (Affinity Capture-MS)

ESM2 similar proteins: A2V9Z4, A6YF56, G3MYZ3, O01454, O35090, O89020, P02768, P02769, P02770, P02771, P02772, P02773, P02774, P04276, P07724, P08759, P08835, P14639, P14872, P19121, P21614, P21847, P21848, P28050, P35747, P36953, P43652, P49064, P49065, P49066, P49822, P53789, P83632, P84407, Q03156, Q17077, Q25513, Q27388, Q28522, Q28789

Diamond homologs: A2V9Z4, A6YF56, G3MYZ3, O35090, O89020, P02768, P02769, P02770, P02771, P02772, P02773, P07724, P08759, P08835, P14639, P14872, P19121, P21847, P28050, P35747, P36953, P43652, P49064, P49065, P49066, P49822, P81188, P84407, P85295, Q28522, Q28789, Q3SZ57, Q3T478, Q5NVH5, Q5XLE4, Q8MJ76, Q8MJU5, P83517, P21848, Q03156

SIGNOR signaling

16 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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	79
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1684642	NC_000004.12:g.67833055_82716065del	Pathogenic
18169	NM_001134.3(AFP):c.883_884del (p.Leu295fs)	Pathogenic
18170	NM_001134.3(AFP):c.543G>A (p.Trp181Ter)	Pathogenic
929747	NM_001134.3(AFP):c.1822G>A (p.Gly608Arg)	Likely pathogenic

SpliceAI

1710 predictions. Top by Δscore:

Variant	Effect	Δscore
4:73438172:A:AG	acceptor_gain	1.0000
4:73438173:G:GG	acceptor_gain	1.0000
4:73438305:AGG:A	donor_loss	1.0000
4:73438306:GGT:G	donor_loss	1.0000
4:73438307:G:C	donor_loss	1.0000
4:73440814:G:GG	donor_gain	1.0000
4:73443342:TCTA:T	acceptor_loss	1.0000
4:73443343:CTA:C	acceptor_loss	1.0000
4:73443344:TA:T	acceptor_loss	1.0000
4:73443345:A:C	acceptor_loss	1.0000
4:73443440:GCCAT:G	donor_gain	1.0000
4:73443444:TG:T	donor_loss	1.0000
4:73443445:G:GA	donor_loss	1.0000
4:73443445:G:GG	donor_gain	1.0000
4:73443446:TAA:T	donor_loss	1.0000
4:73445117:G:GT	donor_gain	1.0000
4:73445148:G:GT	donor_gain	1.0000
4:73447551:TCA:T	donor_gain	1.0000
4:73449326:A:AG	acceptor_gain	1.0000
4:73449327:T:G	acceptor_gain	1.0000
4:73449329:T:G	acceptor_gain	1.0000
4:73449332:CAGT:C	acceptor_loss	1.0000
4:73449333:A:AG	acceptor_gain	1.0000
4:73449333:AGTTT:A	acceptor_loss	1.0000
4:73449334:G:GA	acceptor_gain	1.0000
4:73449334:GT:G	acceptor_gain	1.0000
4:73449334:GTT:G	acceptor_gain	1.0000
4:73449334:GTTT:G	acceptor_gain	1.0000
4:73449334:GTTTT:G	acceptor_gain	1.0000
4:73449460:A:G	donor_gain	1.0000

AlphaMissense

4020 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:73445009:A:C	S244R	0.979
4:73445011:T:A	S244R	0.979
4:73445011:T:G	S244R	0.979
4:73452473:T:A	C501S	0.973
4:73452474:G:C	C501S	0.973
4:73453779:T:C	L556P	0.969
4:73452425:T:A	C485S	0.961
4:73452426:G:C	C485S	0.961
4:73445087:T:A	C270S	0.960
4:73445088:G:C	C270S	0.960
4:73447555:T:A	C313S	0.960
4:73447556:G:C	C313S	0.960
4:73440718:A:C	K129N	0.959
4:73440718:A:T	K129N	0.959
4:73452470:T:A	C500S	0.959
4:73452471:G:C	C500S	0.959
4:73445110:T:G	C277W	0.958
4:73452425:T:C	C485R	0.955
4:73452470:T:C	C500R	0.954
4:73445108:T:C	C277R	0.952
4:73452475:C:G	C501W	0.952
4:73452474:G:A	C501Y	0.950
4:73452426:G:A	C485Y	0.947
4:73452473:T:C	C501R	0.947
4:73443401:T:A	C224S	0.946
4:73443402:G:C	C224S	0.946
4:73447483:T:A	C289S	0.946
4:73447484:G:C	C289S	0.946
4:73447525:T:A	C303S	0.946
4:73447526:G:C	C303S	0.946

dbSNP variants (sampled 300 via entrez): RS1000230878 (4:73435819 G>T), RS10002756 (4:73454177 C>T), RS1000283338 (4:73436187 A>C), RS1000432916 (4:73443018 A>G), RS1000439786 (4:73436815 A>G), RS1000591695 (4:73448441 G>C), RS1000822816 (4:73454419 C>T), RS1000841747 (4:73443089 G>C), RS1000867035 (4:73442676 G>A), RS1000941537 (4:73454772 T>G), RS1001116676 (4:73445730 G>A), RS1001123565 (4:73455749 A>G), RS1001274097 (4:73442946 T>C), RS1001358272 (4:73449594 T>C,G), RS10015577 (4:73445681 G>A,T)

Disease associations

OMIM: gene MIM:104150 | disease phenotypes:

GenCC curated gene-disease

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

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 total (4 of 4 shown, 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 (top):

Study	Trait	p-value
GCST001808_10	Tumor biomarkers	3.000000e-18
GCST001942_8	Prostate cancer	5.000000e-13
GCST006585_2245	Blood protein levels	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005127	cancer biomarker measurement

MeSH disease descriptors (2)

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)

PharmGKB: 1 entry (VIP=true, CPIC=false)

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 expression, decreases reaction, increases 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	decreases expression, affects binding, increases expression, affects cotreatment	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	decreases expression, affects cotreatment	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)

75 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	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