SERPINA2

Summary

SERPINA2 (serpin family A member 2 (gene/pseudogene), HGNC:8985) is a protein-coding gene on chromosome 14q32.13, encoding Alpha-1-antitrypsin-related protein (P20848). Putative serine protease inhibitor.

This gene encodes a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. The encoded intracellular glycoprotein is localized at the endoplasmic reticulum. This gene is a polymorphic pseudogene, with the non-functional allele being predominant in some populations. Some individuals, as represented by the reference genome allele, contain a 2kb coding region deletion and a start code mutation.

Source: NCBI Gene 390502 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Phenotypes (HPO): 84
• Druggable target: yes — 1 molecules with ChEMBL bioactivity

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8985
Approved symbol	SERPINA2
Name	serpin family A member 2 (gene/pseudogene)
Location	14q32.13
Locus type	gene with protein product
Status	Approved
Aliases	ATR, ARGS
Ensembl gene	ENSG00000258597
Ensembl biotype	protein_coding
OMIM	107410
Entrez	390502

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding_LoF

ENST00000553483

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000553483 — 2 exons

Exon	Start	End
ENSE00002522842	94366044	94366698
ENSE00003726472	94364316	94364588

Expression profiles

Bgee: expression breadth broad, 14 present calls, max score 79.37.

Top tissues by expression

117 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	79.37	silver quality
granulocyte	CL:0000094	55.62	gold quality
liver	UBERON:0002107	46.15	gold quality
blood	UBERON:0000178	44.53	gold quality
right lobe of liver	UBERON:0001114	38.70	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
leukocyte	CL:0000738	36.31	silver quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	34.93	gold quality
monocyte	CL:0000576	34.71	silver quality
vermiform appendix	UBERON:0001154	34.17	gold quality
bone marrow	UBERON:0002371	33.24	gold quality
muscle tissue	UBERON:0002385	32.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
islet of Langerhans	UBERON:0000006	31.71	silver quality
sural nerve	UBERON:0015488	30.93	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	29.46	silver quality
prefrontal cortex	UBERON:0000451	29.04	gold quality
duodenum	UBERON:0002114	28.14	gold quality
placenta	UBERON:0001987	27.59	gold quality
lymph node	UBERON:0000029	27.57	gold quality
left uterine tube	UBERON:0001303	27.32	silver quality
tonsil	UBERON:0002372	27.05	gold quality
urinary bladder	UBERON:0001255	26.84	gold quality
gall bladder	UBERON:0002110	25.98	gold quality
right lung	UBERON:0002167	25.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.22

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Study found that a common haplotype in Africa had a 2-kb deletion in the SERPINA2 gene is associated with remarkable long-range homozygozity as if it was quickly driven to high frequency by natural selection acting on an advantageous variant. (PMID:17135331)
• Specific features of SERPINA2 include the absence of insoluble aggregates and the insignificant response to cell stress, suggesting that it is a non-polymerogenic protein with divergent activity of SERPINA1. (PMID:23826168)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Serpina1f	ENSMUSG00000021081
rattus_norvegicus	Serpina1f	ENSRNOG00000037762
rattus_norvegicus	Serpina1fl2	ENSRNOG00000064752

Paralogs (36): SERPINB1 (ENSG00000021355), SERPINB3 (ENSG00000057149), SERPIND1 (ENSG00000099937), SERPINA4 (ENSG00000100665), SERPINE1 (ENSG00000106366), SERPINI2 (ENSG00000114204), SERPINC1 (ENSG00000117601), SERPINA7 (ENSG00000123561), SERPINB6 (ENSG00000124570), SERPINF1 (ENSG00000132386), 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)

Protein

Protein identifiers

Alpha-1-antitrypsin-related protein — P20848 (reviewed: P20848)

Alternative names: Protease inhibitor 1-like, Serpin A2

All UniProt accessions (1): A0A0U1RQB8

UniProt curated annotations — full annotation on UniProt →

Function. Putative serine protease inhibitor.

Subunit / interactions. Interacts with CANX and PDIA3.

Subcellular location. Endoplasmic reticulum.

Tissue specificity. Expressed in the liver, leukocytes and testis. Also detected in brain, colon, uterus, esophagus, spleen, trachea, kidney and lung.

Post-translational modifications. Glycosylated.

Domain organisation. The reactive center loop (RCL) extends out from the body of the protein and directs binding to the target protease. The protease cleaves the serpin at the reactive site within the RCL, establishing a covalent linkage between the carboxyl group of the serpin reactive site and the serine hydroxyl of the protease. The resulting inactive serpin-protease complex is highly stable.

Polymorphism. The SERPINA2 gene is highly polymorphic. Deletions, frameshift mutations and a critical start codon variation (ATG->ATA, dbSNP:rs1956172) have been found in some populations. Population studies suggest that a pseudogenization process may be ongoing in humans. 3 potentially functional alleles, V1, V2 and V3, have been described in the literature. The sequence shown in this entry is that of allele V2.

Similarity. Belongs to the serpin family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00079

UniProt features (15 total): sequence conflict 6, glycosylation site 4, sequence variant 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20848-F1	84.60	0.67

Functional residue map

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

Catalytic / active sites (1): 385–386 (reactive bond)

Glycosylation sites (4): 56, 110, 148, 274

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 522 (showing top): PID_FANCONI_PATHWAY, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_MEIOTIC_SYNAPSIS, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_MEMBRANE_DISASSEMBLY

GO Biological Process (0):

GO Molecular Function (1): serine-type endopeptidase inhibitor activity (GO:0004867)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

10 interactions, top by confidence:

A	B	Type	Score
NRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
KRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
KRAS		psi-mi:“MI:0914”(association)	0.350
BUD13	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
SBDS	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
SF3B4	MED19	psi-mi:“MI:2364”(proximity)	0.270
ZNF800	MED19	psi-mi:“MI:2364”(proximity)	0.270
DDX6	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

ESM2 similar proteins: A2I7M9, A2I7N0, A2I7N1, A2I7N2, A2I7N3, A6QPQ2, B2D1U1, E1BF81, O54762, P01009, P01011, P05154, P05544, P05545, P07758, P07759, P08185, P09006, P20848, P22323, P22324, P22325, P22599, P26595, P29621, P29622, P49920, P50451, P70458, Q00896, Q00897, Q00898, Q03734, Q3ZEJ6, Q5I2A0, Q5R536, Q5R9E3, Q5RCR2, Q5RCW5, Q60396

Diamond homologs: A2I7M9, A2I7N0, A2I7N1, A2I7N2, A2I7N3, A6QPQ2, B2D1U1, E1BF81, O00394, O54757, O54758, O54759, O54760, O54761, O54762, O54763, O75830, P01009, P01010, P01011, P05154, P05543, P05544, P05545, P05619, P07758, P07759, P08185, P09005, P09006, P12725, P17475, P20848, P22323, P22324, P22325, P22599, P23035, P23775, P26595

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

69 predictions. Top by Δscore:

Variant	Effect	Δscore
14:94366039:CTTA:C	donor_loss	1.0000
14:94366040:TTA:T	donor_loss	1.0000
14:94366041:TA:T	donor_loss	1.0000
14:94366042:A:AC	donor_gain	1.0000
14:94366042:A:AT	donor_loss	1.0000
14:94366043:C:CA	donor_loss	1.0000
14:94366043:C:CC	donor_gain	1.0000
14:94364584:CTTGC:C	acceptor_gain	0.9900
14:94364589:C:CC	acceptor_gain	0.9900
14:94364590:T:C	acceptor_loss	0.9900
14:94364585:TTGC:T	acceptor_gain	0.9800
14:94364586:TGC:T	acceptor_gain	0.9800
14:94366110:C:CT	donor_gain	0.9800
14:94366111:T:TT	donor_gain	0.9800
14:94364587:GC:G	acceptor_gain	0.9700
14:94364588:CC:C	acceptor_gain	0.9700
14:94366120:T:TA	donor_gain	0.9700
14:94366042:AC:A	donor_gain	0.9500
14:94366043:CC:C	donor_gain	0.9500
14:94366062:C:CT	donor_gain	0.9300
14:94364685:C:A	donor_gain	0.9200
14:94366035:C:CT	donor_gain	0.9200
14:94366036:T:TT	donor_gain	0.9200
14:94366034:G:GC	donor_gain	0.9100
14:94366040:TTACC:T	donor_gain	0.9100
14:94366041:TACCG:T	donor_gain	0.9100
14:94366042:ACCGT:A	donor_gain	0.9100
14:94366043:C:T	donor_gain	0.9000
14:94366044:C:G	donor_gain	0.8600
14:94366063:C:CT	donor_gain	0.8600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1001075169 (14:94365050 G>C), RS1001122925 (14:94367545 A>G), RS1001152712 (14:94363290 C>A), RS1002593112 (14:94368618 C>T), RS1003154435 (14:94365107 C>T), RS1003518881 (14:94363344 C>T), RS1004182149 (14:94368565 C>T), RS1005329409 (14:94365468 C>T), RS1005403654 (14:94366702 C>T), RS1005487035 (14:94367116 C>T), RS1006072452 (14:94364037 C>T), RS1006149991 (14:94365148 C>G,T), RS1006188655 (14:94366202 T>C), RS1007001495 (14:94366565 C>A), RS1007296285 (14:94364143 C>A,T)

Disease associations

OMIM: gene MIM:107410 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

84 total (30 of 84 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000237	Small anterior fontanelle
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000324	Facial asymmetry
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000387	Absent earlobe
HP:0000444	Convex nasal ridge
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000581	Blepharophimosis
HP:0000670	Carious teeth
HP:0000678	Dental crowding
HP:0000682	Abnormal dental enamel morphology
HP:0000689	Dental malocclusion
HP:0000752	Hyperactivity
HP:0000878	11 pairs of ribs
HP:0000954	Single transverse palmar crease
HP:0001009	Telangiectasia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005194_150	Coronary artery disease	5.000000e-10
GCST005195_77	Coronary artery disease	8.000000e-10
GCST007615_3	C-reactive protein levels	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879431 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,265 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3989870	BERZOSERTIB	2	1,265

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 9 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	BERZOSERTIB
7.70	IC50	20	nM	CHEMBL5596626
6.19	IC50	641	nM	CHEMBL4875626
5.63	IC50	2360	nM	CHEMBL4851439
5.54	IC50	2890	nM	CHEMBL4860779
5.39	IC50	4080	nM	CHEMBL4849035
5.22	IC50	6000	nM	CHEMBL4850640
5.21	IC50	6160	nM	CHEMBL4871998
5.08	IC50	8300	nM	CHEMBL4873263

PubChem BioAssay actives

9 with measured affinity, of 13 total; 9 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1876294: Binding affinity to ATR (unknown origin)	ic50	0.0002	uM
2-methyl-2-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)propanenitrile	2122174: Inhibition of ATR (unknown origin)	ic50	0.0200	uM
1-(cyclohexen-1-yl)-8-[5-(difluoromethyl)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]quinoxaline	1779784: Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	ic50	0.6410	uM
8-[5-(difluoromethyl)-3-pyridinyl]-1-(2,3,6,7-tetrahydrooxepin-4-yl)-[1,2,4]triazolo[4,3-a]quinoxaline	1779784: Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	ic50	2.3600	uM
1-(cyclohepten-1-yl)-8-[5-(difluoromethyl)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]quinoxaline	1779784: Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	ic50	2.8900	uM
8-[5-(difluoromethyl)-3-pyridinyl]-1-(3,6-dihydro-2H-pyran-4-yl)-[1,2,4]triazolo[4,3-a]quinoxaline	1779784: Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	ic50	4.0800	uM
8-[5-(difluoromethyl)-3-pyridinyl]-1-(4-methoxycyclohexyl)-[1,2,4]triazolo[4,3-a]quinoxaline	1779784: Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	ic50	6.0000	uM
1-[(1S,5R)-6-bicyclo[3.1.0]hexanyl]-8-[5-(difluoromethyl)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]quinoxaline	1779784: Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	ic50	6.1600	uM
8-[5-(difluoromethyl)-3-pyridinyl]-1-[(1R,5S)-3-oxabicyclo[3.1.0]hexan-6-yl]-[1,2,4]triazolo[4,3-a]quinoxaline	1779784: Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	ic50	8.3000	uM

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
abrine	increases expression	1
Dust	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1

ChEMBL screening assays

5 unique, capped per target: 3 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4839371	Binding	Inhibition of ATR in human HT29 cells assessed as reduction in gammaH2AX phosphorylation incubated for 30 mins by fluorescence assay	BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies. — J Med Chem
CHEMBL5159408	Functional	In vivo inhibition of ATR in human LoVo cells xenografted in NOD/SCID mouse assessed as inhibition of ATR phosphorylation at 50 to 100 mg/kg, po administered twice a day for 30 days by Western blot analysis	Discovery of a potent and highly selective inhibitor of ataxia telangiectasia mutated and Rad3-Related (ATR) kinase: Structural activity relationship and antitumor activity both in vitro and in vivo. — Eur J Med Chem

Clinical trials (associated diseases)

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