SERPINF1

Summary

SERPINF1 (serpin family F member 1, HGNC:8824) is a protein-coding gene on chromosome 17p13.3, encoding Pigment epithelium-derived factor (P36955). Neurotrophic protein; induces extensive neuronal differentiation in retinoblastoma cells.

This gene encodes a member of the serpin family that does not display the serine protease inhibitory activity shown by many of the other serpin proteins. The encoded protein is secreted and strongly inhibits angiogenesis. In addition, this protein is a neurotrophic factor involved in neuronal differentiation in retinoblastoma cells. Mutations in this gene were found in individuals with osteogenesis imperfecta, type VI.

Source: NCBI Gene 5176 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteogenesis imperfecta type 6 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 388 total — 34 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_002615

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8824
Approved symbol	SERPINF1
Name	serpin family F member 1
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	EPC-1, PIG35
Ensembl gene	ENSG00000132386
Ensembl biotype	protein_coding
OMIM	172860
Entrez	5176

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 24 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000254722, ENST00000570731, ENST00000570820, ENST00000571149, ENST00000571360, ENST00000571870, ENST00000572048, ENST00000572517, ENST00000573763, ENST00000573770, ENST00000576406, ENST00000577053, ENST00000869424, ENST00000869425, ENST00000869426, ENST00000869427, ENST00000869428, ENST00000869429, ENST00000869430, ENST00000869431, ENST00000869432, ENST00000869433, ENST00000869434, ENST00000869435, ENST00000928382, ENST00000960886, ENST00000960887, ENST00000960888

RefSeq mRNA: 4 — MANE Select: NM_002615 NM_001329903, NM_001329904, NM_001329905, NM_002615

CCDS: CCDS11012

Canonical transcript exons

ENST00000254722 — 8 exons

Exon	Start	End
ENSE00000904180	1775058	1775200
ENSE00001132115	1776532	1776742
ENSE00001376201	1762060	1762113
ENSE00002663113	1777187	1777565
ENSE00003472501	1771872	1772075
ENSE00003543071	1771029	1771184
ENSE00003641322	1766903	1766994
ENSE00003677982	1769852	1770050

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 134.4285 / max 3918.1287, expressed in 1410 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158759	109.7932	1182
158757	11.9640	1078
158758	5.5242	871
158772	4.7379	285
158764	0.6621	287
158761	0.5250	193
158760	0.4503	182
158765	0.4498	187
158766	0.1391	54
158770	0.0724	22

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.98	gold quality
pericardium	UBERON:0002407	99.89	gold quality
endocervix	UBERON:0000458	99.68	gold quality
left uterine tube	UBERON:0001303	99.60	gold quality
gall bladder	UBERON:0002110	99.60	gold quality
periodontal ligament	UBERON:0008266	99.59	gold quality
vena cava	UBERON:0004087	99.58	gold quality
right ovary	UBERON:0002118	99.57	gold quality
right lobe of liver	UBERON:0001114	99.56	gold quality
mucosa of stomach	UBERON:0001199	99.52	gold quality
adipose tissue	UBERON:0001013	99.51	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.50	gold quality
liver	UBERON:0002107	99.49	gold quality
peritoneum	UBERON:0002358	99.49	gold quality
choroid plexus epithelium	UBERON:0003911	99.49	gold quality
omental fat pad	UBERON:0010414	99.49	gold quality
left ovary	UBERON:0002119	99.48	gold quality
synovial joint	UBERON:0002217	99.48	gold quality
body of uterus	UBERON:0009853	99.47	gold quality
right testis	UBERON:0004534	99.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.40	gold quality
tibial nerve	UBERON:0001323	99.39	gold quality
cauda epididymis	UBERON:0004360	99.37	gold quality
connective tissue	UBERON:0002384	99.35	gold quality
right coronary artery	UBERON:0001625	99.33	gold quality
urethra	UBERON:0000057	99.31	gold quality
left testis	UBERON:0004533	99.31	gold quality
coronary artery	UBERON:0001621	99.28	gold quality
calcaneal tendon	UBERON:0003701	99.28	gold quality
skin of hip	UBERON:0001554	99.26	gold quality

Single-cell (SCXA)

Detected in 40 experiment(s), a significant marker in 39.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	10591.27
E-MTAB-11121	yes	7972.51
E-CURD-112	yes	3018.40
E-HCAD-15	yes	2662.70
E-CURD-126	yes	2586.56
E-MTAB-6701	yes	2355.77
E-HCAD-24	yes	2140.55
E-MTAB-9841	yes	2105.39
E-MTAB-10287	yes	1888.82
E-HCAD-11	yes	1860.08
E-MTAB-8410	yes	1699.82
E-MTAB-6678	yes	1685.15
E-CURD-114	yes	1643.82
E-MTAB-10137	yes	1322.10
E-MTAB-6108	yes	1197.34

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HES1	Activation
HES5	Activation

Upstream regulators (CollecTRI, top): GATA3, MITF, NCOR1, NFATC2, PARP1, RARA, TP53, TP63, TP73

miRNA regulators (miRDB)

9 targeting SERPINF1, 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-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-6796-3P	98.68	65.49	689
HSA-MIR-675-3P	95.77	69.27	675
HSA-MIR-6774-3P	89.14	65.20	68

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• role of PEDF in protecting retinal pericytes from oxidant injury (PMID:12200129)
• Results describe the first collagen-binding site described for a serpin, pigment epithelium-derived factor (PEDF), which is distinct from its heparin-binding region, neurotrophic active site, and its serpin exposed loop. (PMID:12237317)
• EPC-1 may play a role in the entry of early passage fibroblasts into a G(0) state or the maintenance of such a state once reached (PMID:12599204)
• reactive center loop, specifically Gly376 and Leu377, is involved in the interaction of PEDF with components of the quality control system in the endoplasmic reticulum, thus ensuring its efficient secretion (PMID:12603315)
• VEGF secreted by retinal pigment epithelial cells upregulates pigment epithelium-derived factor expression via VEGFR-1 in an autocrine manner. (PMID:12670505)
• pigment epithelium-derived factor content in the aqueous humor of diabetic patients strongly predicts who among them will develop progression of retinopathy (PMID:12687338)
• PEDF may block the angiogenic effects of leptin through its anti-oxidative properties (PMID:12711260)
• Present in plasma at approx. 100 nM (5 microg/ml) or twice the level required to inhibit aberrant blood-vessel growth in the eye (PMID:12737624)
• Pterygia exhibit significantly lower PEDF but higher VEGF levels than those in normal corneas and conjunctivae. The decreased PEDF level in pterygia may play a role in the formation and progression of pterygia. (PMID:12827055)
• human oral squamous cell carcinoma cells produce VEGF, which in turn regulates PEDF production, and this balance may be contributing to neovascularization in tumors. (PMID:12860293)
• Gene transfer of pigment epithelium-derived factor suppresses tumor vascularization and growth, while prolonging survival in syngeneic murine models of thoracic malignancies. (PMID:12878936)
• level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) is inversely associated with proliferative retinopathy (PMID:12920663)
• Malignant peripheral nerve sheath tumors (MPNST) Schwann cells lose the ability to downregulate PEDF upon axonal contact. (PMID:14991838)
• effectively abates vascular endothelial growth factor-induced vascular permeability (PMID:15096582)
• potential role of the age-associated decline in EPC-1 expression in tissue remodeling and in the development of skin diseases with excessive angiogenesis (PMID:15140209)
• PEDF expression suggests a more favorable prognosis than in patients with ductal pancreatic adenocarcinomas. (PMID:15150108)
• Role in angiogenesis of hepatocellular carcinoma(HCC). Reduction of serum PEDF concentration associated with development of chronic liver diseases may contribute to progression of HCC. Gene therapy using PEDF may be efficient treatment for HCC. (PMID:15239109)
• novel role of extracellular phosphorylation is shown here to completely change the nature of PEDF from a neutrophic to an antiangiogenic factor. (PMID:15374885)
• PEDF-6 affects different second messenger biosynthesis systems in HL-60 cells. and inhibits phosphatidylinositol-specific phospholipase C stimulated by aluminum tetrafluoride anions (PMID:15377265)
• PEDF downregulates Fyn through Fes, resulting in inhibition of FGF-2-induced capillary morphogenesis of endothelial cells (PMID:15713745)
• PEDF inhibits Ang-II-induced EC activation by suppressing NADPH-oxidase-mediated ROS generation and that PEDF may play a protective role in the development (PMID:15846509)
• PEDF gene contains a response element specific for p63 and p73 in its promoter region (PMID:15856012)
• PEDF may play a significant role in determining the balance of angiogenesis/ antiangiogenesis during atherogenesis (PMID:15994443)
• In tumor xenografts, the overexpression of wild-type PEDF significantly suppressed tumor growth, whereas a mutant of the collagen I-binding site of PEDF (Col-mut PEDF) did not inhibit tumor growth (PMID:16102727)
• In painless neuropathies, there is decreased level of PEDF in cerebrospinl fluid, compared with patients with painful neuropathies. (PMID:16196102)
• Phosphorylation induces variable effects of PEDF, and therefore contributes to the complexity of PEDF action, shich might be used to generate effective antiangiogenic or neurotrophic drugs. (PMID:16322471)
• REVIEW: this paper describes the unbalanced expressions of VEGF and PEDF as a cause of CNV (PMID:16409998)
• Results show that low levels of PEDF in lung tumor tissues was associated with a significantly shorter survival. (PMID:16596284)
• Central mechanism for PEDF inhibition of the AGE signaling to vascular permeability is by suppression of NADPH oxidase-mediated reactive oxygen species generation and subsequent VEGF expression. (PMID:16707486)
• These observations collectively support the hypothesis that a lack of PEDF expression is a potent factor for the enhancement of tumor growth and angiogenesis in breast cancer. (PMID:16740777)
• study is the first to demonstrate a role of pigment epithelium-derived factor (PEDF) in ovarian surface epithelium biology and ovarian cancer and suggests that the loss of PEDF may be of relevance in carcinogenesis (PMID:16777976)
• PEDF may play a protective role against early diabetic retinopathy by attenuating the deleterious effect of AGE (PMID:16797605)
• The analysis of the promoter region of the EPC-1/PEDF gene in this paper suggests the age- and cell cycle-dependent expression of specific transcriptional factor(s). (PMID:16896539)
• Increase in serum PEDF during ulcerative colitis, especially in severe forms of disease suggests its involvement in ulcerative colitis pathogenesis. (PMID:17188371)
• heparin induces a conformational change in the vicinity of Lys(178) (PMID:17202143)
• High levels of PEDF in the plasma may be related to the progression of diabetic retinopathy. (PMID:17213275)
• PEDF-overexpressing tumors exhibited reduced intratumoral angiogenesis, and PEDF may be a new and promising approach for the treatment of osteosarcoma. (PMID:17479108)
• These results demonstrate that PEDF could inhibit neointimal formation via suppression of NADPH oxidase-mediated reactive oxygen species generation. (PMID:17525281)
• hepatic PEDF levels may be elevated to counteract the effects of oxidative stress (PMID:17593873)
• The correlation between PEDF and VEGF striatal levels in PD patients suggests that concerted neurotrophic functions of these factors or structural changes in blood vessel walls play an important role in the pathophysiology of PD. (PMID:17604022)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	serpinf1	ENSDARG00000069048
mus_musculus	Serpinf1	ENSMUSG00000000753
rattus_norvegicus	Serpinf1	ENSRNOG00000003172

Paralogs (36): SERPINB1 (ENSG00000021355), SERPINB3 (ENSG00000057149), SERPIND1 (ENSG00000099937), SERPINA4 (ENSG00000100665), SERPINE1 (ENSG00000106366), SERPINI2 (ENSG00000114204), SERPINC1 (ENSG00000117601), SERPINA7 (ENSG00000123561), SERPINB6 (ENSG00000124570), AGT (ENSG00000135744), SERPINE2 (ENSG00000135919), SERPINA10 (ENSG00000140093), SERPING1 (ENSG00000149131), SERPINH1 (ENSG00000149257), SERPINI1 (ENSG00000163536), SERPINA12 (ENSG00000165953), SERPINB7 (ENSG00000166396), SERPINB8 (ENSG00000166401), SERPINB12 (ENSG00000166634), SERPINF2 (ENSG00000167711), SERPINA9 (ENSG00000170054), SERPINA6 (ENSG00000170099), SERPINB9 (ENSG00000170542), SERPINA11 (ENSG00000186910), SERPINA5 (ENSG00000188488), SERPINA3 (ENSG00000196136), SERPINA1 (ENSG00000197249), SERPINB2 (ENSG00000197632), SERPINB13 (ENSG00000197641), SERPINB11 (ENSG00000206072), SERPINB4 (ENSG00000206073), SERPINB5 (ENSG00000206075), HMSD (ENSG00000221887), SERPINB10 (ENSG00000242550), SERPINE3 (ENSG00000253309), SERPINA2 (ENSG00000258597)

Protein

Protein identifiers

Pigment epithelium-derived factor — P36955 (reviewed: P36955)

Alternative names: Cell proliferation-inducing gene 35 protein, EPC-1, Serpin F1

All UniProt accessions (10): P36955, A0A140VKF3, I3L107, I3L1U4, I3L2R7, I3L3Z3, I3L425, I3L4F9, I3L4N7, I3L4Z0

UniProt curated annotations — full annotation on UniProt →

Function. Neurotrophic protein; induces extensive neuronal differentiation in retinoblastoma cells. Potent inhibitor of angiogenesis. As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity.

Subunit / interactions. Interacts with PNPLA2; this interaction stimulates the phospholipase A2 activity of PNPLA2.

Subcellular location. Secreted. Melanosome.

Tissue specificity. Retinal pigment epithelial cells and blood plasma.

Post-translational modifications. The N-terminus is blocked. Extracellular phosphorylation enhances antiangiogenic activity. N- and O-glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.

Disease relevance. Osteogenesis imperfecta 6 (OI6) [MIM:613982] A form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI6 is a severe, autosomal recessive form compatible with OI type III in the Sillence classification. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal (AA 44-121) exhibits neurite outgrowth-inducing activity. The C-terminal exposed loop (AA 382-418) is essential for serpin activity.

Similarity. Belongs to the serpin family.

RefSeq proteins (4): NP_001316832, NP_001316833, NP_001316834, NP_002606* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000215	Serpin_fam	Family
IPR023795	Serpin_CS	Conserved_site
IPR023796	Serpin_dom	Domain
IPR033832	PEDF_serpin_dom	Domain
IPR036186	Serpin_sf	Homologous_superfamily
IPR042178	Serpin_sf_1	Homologous_superfamily
IPR042185	Serpin_sf_2	Homologous_superfamily

Pfam: PF00079

UniProt features (47 total): strand 15, helix 14, turn 6, modified residue 4, sequence variant 2, region of interest 2, signal peptide 1, chain 1, sequence conflict 1, glycosylation site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9J3Q	X-RAY DIFFRACTION	1.9
9J3P	X-RAY DIFFRACTION	2.1
1IMV	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36955-F1	90.86	0.85

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 (4): 20, 24, 114, 227

Glycosylation sites (1): 285

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 355 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, YAATNRNNNYNATT_UNKNOWN, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, TERAMOTO_OPN_TARGETS_CLUSTER_6, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, MARTINEZ_RB1_TARGETS_UP, MODULE_75, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP

GO Biological Process (18): kidney development (GO:0001822), short-term memory (GO:0007614), response to acidic pH (GO:0010447), negative regulation of endothelial cell migration (GO:0010596), negative regulation of gene expression (GO:0010629), positive regulation of neuron projection development (GO:0010976), negative regulation of angiogenesis (GO:0016525), ovulation cycle (GO:0042698), response to arsenic-containing substance (GO:0046685), positive regulation of neurogenesis (GO:0050769), retina development in camera-type eye (GO:0060041), epithelial cell proliferation involved in prostate gland development (GO:0060767), negative regulation of epithelial cell proliferation involved in prostate gland development (GO:0060770), cellular response to cobalt ion (GO:0071279), cellular response to retinoic acid (GO:0071300), cellular response to glucose stimulus (GO:0071333), cellular response to dexamethasone stimulus (GO:0071549), response to peptide (GO:1901652)

GO Molecular Function (2): serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515)

GO Cellular Component (10): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), melanosome (GO:0042470), axon hillock (GO:0043203), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), axon (GO:0030424), neuronal cell body (GO:0043025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to chemical	2
animal organ development	1
renal system development	1
memory	1
response to pH	1
regulation of endothelial cell migration	1
negative regulation of cell migration	1
endothelial cell migration	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
rhythmic process	1
multicellular organismal reproductive process	1
positive regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
positive regulation of nervous system development	1
camera-type eye development	1
anatomical structure development	1
prostate gland development	1
epithelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
negative regulation of developmental process	1
negative regulation of multicellular organismal process	1
epithelial cell proliferation involved in prostate gland development	1
regulation of epithelial cell proliferation involved in prostate gland development	1
negative regulation of reproductive process	1
response to cobalt ion	1
cellular response to metal ion	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
intracellular glucose homeostasis	1

Protein interactions and networks

STRING

1714 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERPINF1	PLG	P00747	995
SERPINF1	A2M	P01023	849
SERPINF1	ALB	P02768	837
SERPINF1	FN1	P02751	828
SERPINF1	CPB2	Q96IY4	816
SERPINF1	PLAT	P00750	816
SERPINF1	VTN	P01141	816
SERPINF1	F2	P00734	785
SERPINF1	CRTAP	O75718	743
SERPINF1	FKBP10	Q96AY3	718
SERPINF1	TMEM38B	Q9NVV0	706
SERPINF1	SERPINA1	P01009	702
SERPINF1	P3H1	Q32P28	685
SERPINF1	IFITM5	A6NNB3	677
SERPINF1	PLAU	P00749	663

IntAct

49 interactions, top by confidence:

A	B	Type	Score
SERPINF1	EPM2AIP1	psi-mi:“MI:0915”(physical association)	0.850
ATP1	ATP2	psi-mi:“MI:0915”(physical association)	0.770
SERPINF1	HSPA5	psi-mi:“MI:0914”(association)	0.620
SERPINF1	L3MBTL2	psi-mi:“MI:0915”(physical association)	0.620
SERPINF1	HSPA5	psi-mi:“MI:0915”(physical association)	0.620
SERPINF1	IMPACT	psi-mi:“MI:0915”(physical association)	0.560
SERPINF1	SGTB	psi-mi:“MI:0915”(physical association)	0.560
ATP15	ATP2	psi-mi:“MI:0915”(physical association)	0.560
SERPINA6	COCH	psi-mi:“MI:0914”(association)	0.530
SERPINF1	ATP2	psi-mi:“MI:0915”(physical association)	0.400
PCNA	SERPINF1	psi-mi:“MI:0915”(physical association)	0.370
SERPINF1	PTPN11	psi-mi:“MI:0915”(physical association)	0.370
MLH1	SERPINF1	psi-mi:“MI:0915”(physical association)	0.370
RET	PIK3R2	psi-mi:“MI:0914”(association)	0.350
MAPT	SEPTIN8	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
TMEM25	NME4	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): SERPINF1 (Reconstituted Complex), EPM2AIP1 (Two-hybrid), SERPINF1 (Affinity Capture-MS), SERPINF1 (Affinity Capture-MS), EPM2AIP1 (Two-hybrid), L3MBTL2 (Affinity Capture-MS), KLHL8 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), SERPINF1 (Two-hybrid), SERPINF1 (Reconstituted Complex), IMPACT (Two-hybrid), EPM2AIP1 (Two-hybrid), SGTB (Two-hybrid), SERPINF1 (Affinity Capture-MS)

ESM2 similar proteins: A2I7N3, A6QPQ2, A6QQ92, A8MV23, B0UYL8, B2D1U1, E1BF81, P01017, P01019, P05154, P05155, P05545, P07758, P07759, P08185, P08697, P09006, P20757, P22323, P23035, P23775, P26595, P28800, P29621, P29622, P36955, P49920, P50448, P50451, P97298, Q00896, Q00898, Q03734, Q09055, Q5I2A0, Q5R9E3, Q5RDA8, Q60396, Q61247, Q63556

Diamond homologs: A0A090BX51, A0A0K8RJ89, A0A0K8RJV9, A2I7M9, A2I7N0, A2I7N1, O54757, O54758, O54759, O54760, P05545, P05619, P06293, P07759, P08697, P09005, P14369, P22323, P23035, P26595, P28800, P30740, P32759, P36955, P50448, P80229, P97298, Q03734, Q1JPB0, Q3ZEJ6, Q40066, Q4G075, Q52L45, Q5I0S8, Q5I2A0, Q5R536, Q5SV42, Q60396, Q61247, Q63556

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MITF	“up-regulates quantity by expression”	SERPINF1	“transcriptional regulation”
PARP1	“down-regulates quantity by repression”	SERPINF1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	21
Uncertain significance	132
Likely benign	125
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064530	NM_002615.7(SERPINF1):c.838_839del (p.Leu280fs)	Pathogenic
1342706	NM_002615.7(SERPINF1):c.77dup (p.Glu27fs)	Pathogenic
1366669	NC_000017.10:g.(?1679209)(1680740_?)del	Pathogenic
1445232	NM_002615.7(SERPINF1):c.1024del (p.Asp342fs)	Pathogenic
1454957	NM_002615.7(SERPINF1):c.925C>T (p.Gln309Ter)	Pathogenic
1922504	NM_002615.7(SERPINF1):c.349_356dup (p.His119fs)	Pathogenic
1962411	NM_002615.7(SERPINF1):c.553C>T (p.Gln185Ter)	Pathogenic
2023031	NM_002615.7(SERPINF1):c.1008del (p.Leu337fs)	Pathogenic
2025191	NM_002615.7(SERPINF1):c.843del (p.Lys281_Val282insTer)	Pathogenic
2058617	NM_002615.7(SERPINF1):c.734C>A (p.Ser245Ter)	Pathogenic
2137872	NM_002615.7(SERPINF1):c.498_499del (p.Arg167fs)	Pathogenic
2423440	NC_000017.10:g.(?1645209)(1731288_?)del	Pathogenic
2424501	NC_000017.10:g.(?1651872)(1675389_?)del	Pathogenic
2832239	NM_002615.7(SERPINF1):c.604dup (p.Glu202fs)	Pathogenic
3069167	NM_002615.7(SERPINF1):c.532C>T (p.Gln178Ter)	Pathogenic
31851	NM_002615.7(SERPINF1):c.696C>G (p.Tyr232Ter)	Pathogenic
31852	NM_002615.7(SERPINF1):c.324_325dup (p.Tyr109fs)	Pathogenic
31853	NM_002615.7(SERPINF1):c.1132C>T (p.Gln378Ter)	Pathogenic
3243152	NC_000017.10:g.(?1673126)(1673364_?)del	Pathogenic
3243154	NC_000017.10:g.(?1670205)(1675389_?)del	Pathogenic
3581692	NM_002615.7(SERPINF1):c.857_868del (p.Leu286_Glu290delinsTer)	Pathogenic
3618020	NM_002615.7(SERPINF1):c.1096G>T (p.Glu366Ter)	Pathogenic
3653734	NM_002615.7(SERPINF1):c.482C>A (p.Ser161Ter)	Pathogenic
3659278	NM_002615.7(SERPINF1):c.1069del (p.Glu357fs)	Pathogenic
3906952	NM_002615.7(SERPINF1):c.250dup (p.Ser84fs)	Pathogenic
41892	NM_002615.7(SERPINF1):c.119_120del (p.Val40fs)	Pathogenic
41893	NM_002615.7(SERPINF1):c.-9+2dup	Pathogenic
41894	NM_002615.7(SERPINF1):c.653del (p.Val218fs)	Pathogenic
426454	NM_002615.7(SERPINF1):c.295C>T (p.Arg99Ter)	Pathogenic
4531286	NM_002615.7(SERPINF1):c.397C>T (p.Gln133Ter)	Pathogenic

SpliceAI

1339 predictions. Top by Δscore:

Variant	Effect	Δscore
17:1769848:CCAG:C	acceptor_loss	1.0000
17:1769851:G:A	acceptor_loss	1.0000
17:1770046:GCTGG:G	donor_gain	1.0000
17:1770047:CTGGG:C	donor_loss	1.0000
17:1770048:TGGGT:T	donor_loss	1.0000
17:1770049:GG:G	donor_gain	1.0000
17:1770049:GGGTG:G	donor_loss	1.0000
17:1770050:GG:G	donor_gain	1.0000
17:1770050:GGT:G	donor_loss	1.0000
17:1770051:G:GG	donor_gain	1.0000
17:1770052:T:A	donor_loss	1.0000
17:1771023:T:A	acceptor_gain	1.0000
17:1771025:GCA:G	acceptor_loss	1.0000
17:1771027:A:AC	acceptor_loss	1.0000
17:1771027:A:AG	acceptor_gain	1.0000
17:1771027:AG:A	acceptor_gain	1.0000
17:1771028:G:GC	acceptor_gain	1.0000
17:1771028:GG:G	acceptor_gain	1.0000
17:1771028:GGA:G	acceptor_gain	1.0000
17:1771028:GGAGC:G	acceptor_gain	1.0000
17:1771180:GAAGA:G	donor_gain	1.0000
17:1771181:AAGA:A	donor_gain	1.0000
17:1771182:AGA:A	donor_gain	1.0000
17:1771183:GA:G	donor_gain	1.0000
17:1771183:GAG:G	donor_gain	1.0000
17:1771183:GAGT:G	donor_loss	1.0000
17:1771184:AG:A	donor_loss	1.0000
17:1771185:G:GG	donor_gain	1.0000
17:1771185:GTGA:G	donor_loss	1.0000
17:1771186:T:A	donor_loss	1.0000

AlphaMissense

2732 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:1776536:C:A	A264D	0.997
17:1769967:G:C	R67P	0.996
17:1775063:T:A	W217R	0.996
17:1775063:T:C	W217R	0.996
17:1776623:T:A	L293H	0.996
17:1776623:T:C	L293P	0.996
17:1769961:T:C	L65P	0.995
17:1770050:G:A	G95R	0.995
17:1770050:G:C	G95R	0.995
17:1777418:G:A	G410D	0.995
17:1769942:T:C	S59P	0.994
17:1769951:G:C	G62R	0.994
17:1769952:G:A	G62D	0.994
17:1775065:G:C	W217C	0.994
17:1775065:G:T	W217C	0.994
17:1775075:T:C	F221L	0.994
17:1775076:T:G	F221C	0.994
17:1775077:T:A	F221L	0.994
17:1775077:T:G	F221L	0.994
17:1775105:T:C	F231L	0.994
17:1775107:C:A	F231L	0.994
17:1775107:C:G	F231L	0.994
17:1770036:C:G	S90W	0.993
17:1771029:G:A	G95E	0.993
17:1771119:T:C	L125P	0.993
17:1770012:C:G	P82R	0.992
17:1770035:T:C	S90P	0.992
17:1775195:T:C	C261R	0.992
17:1776634:T:C	F297L	0.992
17:1776636:C:A	F297L	0.992

dbSNP variants (sampled 300 via entrez): RS1000403712 (17:1761848 T>C), RS1000502156 (17:1774546 G>A), RS1000648758 (17:1774915 C>G,T), RS1000908502 (17:1766048 C>T), RS1000963407 (17:1762674 G>A), RS1001104125 (17:1766280 G>C), RS1001114611 (17:1767983 C>G), RS1001130631 (17:1770269 G>A), RS1001226014 (17:1767503 G>A,C), RS1001354986 (17:1762903 C>T), RS1001385416 (17:1771518 G>A,C,T), RS1001444072 (17:1767252 C>G), RS1001653710 (17:1771374 G>A,C), RS1001937444 (17:1770291 T>C), RS1001988685 (17:1770146 G>T)

Disease associations

OMIM: gene MIM:172860 | disease phenotypes: MIM:613982, MIM:166200, MIM:166710, MIM:142623, MIM:259420

GenCC curated gene-disease

Disease	Classification	Inheritance
osteogenesis imperfecta type 6	Strong	Autosomal recessive
osteogenesis imperfecta type 3	Supportive	Autosomal dominant
osteogenesis imperfecta type 4	Supportive	Autosomal dominant

Mondo (6): osteogenesis imperfecta type 6 (MONDO:0013515), osteogenesis imperfecta (MONDO:0019019), osteoporosis (MONDO:0005298), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), osteogenesis imperfecta type 3 (MONDO:0009804), osteogenesis imperfecta type 4 (MONDO:0008148)

Orphanet (3): Osteogenesis imperfecta (Orphanet:666), Hirschsprung disease (Orphanet:388), Osteogenesis imperfecta type 3 (Orphanet:216812)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000592	Blue sclerae
HP:0000703	Dentinogenesis imperfecta
HP:0001270	Motor delay
HP:0001382	Joint hypermobility
HP:0002659	Increased susceptibility to fractures
HP:0002757	Recurrent fractures
HP:0002812	Coxa vara
HP:0002953	Vertebral compression fracture
HP:0002979	Bowing of the legs
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003179	Protrusio acetabuli
HP:0003593	Infantile onset
HP:0004568	Beaking of vertebral bodies
HP:0004586	Biconcave vertebral bodies
HP:0006488	Bowing of the arm
HP:0033154	Elevated circulating deoxypyridinoline concentration

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000769_6	Calcium levels	7.000000e-07
GCST006585_2182	Blood protein levels	3.000000e-48
GCST006585_2346	Blood protein levels	5.000000e-49

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
D010024	Osteoporosis	C05.116.198.579; C18.452.104.579
C536044	Osteogenesis imperfecta, type 3 (supp.)
C536047	Osteogenesis imperfecta, type 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295753 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1136287	SERPINF1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	9
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression, increases methylation	6
Aflatoxin B1	increases methylation, affects expression, decreases expression	4
bisphenol A	affects expression, increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, decreases expression	3
Arsenic	increases expression, affects cotreatment, decreases expression, increases abundance	3
Particulate Matter	increases expression, decreases expression, increases abundance	3
Panobinostat	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	increases expression, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
securinine	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
nornicotine	decreases expression	1
deoxynivalenol	decreases expression	1
methylselenic acid	increases expression	1
hydroxyhydroquinone	decreases expression	1
mancozeb	decreases expression	1
cobaltous chloride	affects expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benazol P	affects expression	1
nivalenol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118636	Binding	Binding affinity to SERPINF1 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9RH	Ubigene HEK293 SERPINF1 KO	Transformed cell line	Female
CVCL_TK65	HAP1 SERPINF1 (-) 1	Cancer cell line	Male
CVCL_WS20	C8161-PEDF	Cancer cell line	Female
CVCL_WS25	UCD-Mel-N-PEDF	Cancer cell line	Sex unspecified
CVCL_XS58	HAP1 SERPINF1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT00006180	PHASE4	COMPLETED	Bone Loss in Premenopausal Women With Depression
NCT00035256	PHASE4	COMPLETED	Sequential Use of Teriparatide and Raloxifene HCl in the Treatment of Postmenopausal Women With Osteoporosis
NCT00035971	PHASE4	COMPLETED	EVA: Evista Alendronate Comparison
NCT00114556	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Density in Liver Transplant Patients
NCT00130403	PHASE4	COMPLETED	OPTAMISE: Clinical Effectiveness of Teriparatide After Alendronate or Risedronate Therapy in Osteoporotic Postmenopausal Women
NCT00148915	PHASE4	COMPLETED	A Study To Assess the Quality and Strength of Bone in Women Participants With Osteoporosis Taking Oral Ibandronate Versus Placebo
NCT00157690	PHASE4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00165607	PHASE4	COMPLETED	Randomized, Open, Parallel, Active Controlled Study on Fracture Prevention in Antiosteoporosis Treatment (OF Study)
NCT00168909	PHASE4	COMPLETED	Influence of Alfacalcidol on Falls in Osteopenic/Osteoporotic Postmenopausal Women (ALFA Study)
NCT00182871	PHASE4	COMPLETED	Testosterone Effects on Bone and Frailty
NCT00191425	PHASE4	COMPLETED	2-Year Therapy With Teriparatide vs 1-yr Therapy Followed by 1-Year of Raloxifene or Calcium/Vit D in Severe Postmenopausal Osteoporosis
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00221299	PHASE4	COMPLETED	Risedronate and Parathyroid Hormone to Reverse Osteoporosis Caused by Chronic Steroid Use
NCT00252408	PHASE4	COMPLETED	Danish Osteoporosis Prevention Study
NCT00259298	PHASE4	COMPLETED	Evaluation of the Effects of Teriparatide on Skeleton Images in Postmenopausal Women With Osteoporosis
NCT00261625	PHASE4	COMPLETED	Can Alendronate Suppress Calcification and Improve Bone Density in Chronic Peritoneal Dialysis Patients?
NCT00271713	PHASE4	COMPLETED	Impact of Oral Ibandronate 150 mg Monthly on Structural Properties of Bone in Postmenopausal Osteoporosis (SPIMOS-3D)
NCT00294463	PHASE4	COMPLETED	Effects of Tibolone Treatment on the Endometrium
NCT00327990	PHASE4	COMPLETED	Evaluation Of Missed Osteoporosis Diagnoses, And Preference Between Once Monthly Ibandronate And Once Weekly Alendronate
NCT00357331	PHASE4	COMPLETED	The Effects of Potassium Citrate on Bone Metabolism
NCT00371956	PHASE4	COMPLETED	Raloxifene for Prevention of Bone Loss in Postmenopausal Patients Receiving Chronic Corticosteroid Therapy
NCT00372372	PHASE4	COMPLETED	The Efficacy of Risedronate in Prevention of Bone Loss in Patients Receiving High Dose Corticosteroid Treatment
NCT00376662	PHASE4	COMPLETED	HRT Versus Etidronate for Osteoporosis and Fractures in Asthmatics Receiving Glucocorticoids.
NCT00402441	PHASE4	COMPLETED	Risedronate in the Prevention of Osteoporosis in Postmenopausal Women
NCT00405392	PHASE4	COMPLETED	Study To Investigate Patient Preference On Dosing In Ibandronate And Risedronate In Korean Women With Postmenopausal Osteoporosis
NCT00431444	PHASE4	COMPLETED	Effects of Zoledronic Acid and Raloxifene on Bone Turnover Markers in Postmenopausal Women With Low Bone Mineral Density
NCT00446589	PHASE4	TERMINATED	The Effects of Ibandronate or Teriparatide Therapy on Bone Histology and Biochemical Indices in Patients on Hemodialysis With Low Bone Mineral Density
NCT00453492	PHASE4	COMPLETED	Risedronate Sodium in Post Menopausal Osteoporosis
NCT00460057	PHASE4	COMPLETED	The Change of Bone Markers After Low Dose Alendronate in Postmenopausal Women With Bone Loss
NCT00479037	PHASE4	COMPLETED	Effect of Full Length Parathyroid Hormone, PTH(1-84) or Strontium Ranelate on Bone Markers in Postmenopausal Women With Primary Osteoporosis (FP-006-IM)
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00489424	PHASE4	COMPLETED	Acetaminophen or Fluvastatin Compared to Placebo on the Transient Post-Dose Symptoms (PDS) Following an Intravenous (i.v.) Infusion of a Single Dose of Zoledronic Acid 5mg, in Post-menopausal Women With Low Bone Mass
NCT00491920	PHASE4	COMPLETED	High Dosage Vitamin D and Osteoporosis
NCT00504166	PHASE4	COMPLETED	Alendronate Prevents Microarchitectural Deterioration of Trabecular Bone in Early Postmenopausal Women