SPRR2A

Summary

SPRR2A (small proline rich protein 2A, HGNC:11261) is a protein-coding gene on chromosome 1q21.3, encoding Small proline-rich protein 2A (P35326). Gut bactericidal protein that selectively kills Gram-positive bacteria by binding to negatively charged lipids on bacterial membranes, leading to bacterial membrane permeabilization and disruption.

Enables lipid binding activity. Involved in antibacterial humoral response and defense response to Gram-positive bacterium. Located in cytoplasm. Is active in extracellular region and secretory granule.

Source: NCBI Gene 6700 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 10 total
• MANE Select transcript: NM_005988

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11261
Approved symbol	SPRR2A
Name	small proline rich protein 2A
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000241794
Ensembl biotype	protein_coding
OMIM	182267
Entrez	6700

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000392653

RefSeq mRNA: 1 — MANE Select: NM_005988 NM_005988

CCDS: CCDS1034

Canonical transcript exons

ENST00000392653 — 2 exons

Exon	Start	End
ENSE00001447899	153057471	153057512
ENSE00001821843	153056120	153056754

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 99.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 17.2425 / max 8098.5777, expressed in 124 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14585	17.2425	124
14593	0.0350	3
201737	0.0138	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.93	gold quality
lower esophagus mucosa	UBERON:0035834	99.90	gold quality
esophagus squamous epithelium	UBERON:0006920	99.88	gold quality
gingiva	UBERON:0001828	99.87	gold quality
gingival epithelium	UBERON:0001949	99.83	gold quality
body of tongue	UBERON:0011876	99.79	gold quality
amniotic fluid	UBERON:0000173	99.76	gold quality
pharyngeal mucosa	UBERON:0000355	99.69	gold quality
esophagus mucosa	UBERON:0002469	99.53	gold quality
oral cavity	UBERON:0000167	98.93	gold quality
penis	UBERON:0000989	98.32	gold quality
tongue	UBERON:0001723	97.51	gold quality
nasal cavity epithelium	UBERON:0005384	95.89	gold quality
mammalian vulva	UBERON:0000997	94.31	gold quality
superior surface of tongue	UBERON:0007371	94.04	gold quality
palpebral conjunctiva	UBERON:0001812	92.63	gold quality
sperm	CL:0000019	89.85	gold quality
vagina	UBERON:0000996	88.80	gold quality
esophagus	UBERON:0001043	85.88	gold quality
epithelium of nasopharynx	UBERON:0001951	83.44	gold quality
tonsil	UBERON:0002372	82.89	gold quality
upper leg skin	UBERON:0004262	82.19	gold quality
mouth mucosa	UBERON:0003729	79.66	gold quality
ectocervix	UBERON:0012249	79.33	gold quality
pancreatic ductal cell	CL:0002079	79.05	silver quality
minor salivary gland	UBERON:0001830	76.73	gold quality
uterine cervix	UBERON:0000002	74.86	gold quality
nipple	UBERON:0002030	73.37	gold quality
right coronary artery	UBERON:0001625	71.87	gold quality
nasal cavity mucosa	UBERON:0001826	70.91	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	9609.37
E-MTAB-10596	yes	5037.48
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELF3, GLI2, JUN, KLF4, NKX3-1, POU2F3, SP1, STAT5A, STAT5B

miRNA regulators (miRDB)

25 targeting SPRR2A, 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-6764-5P	99.75	67.89	2304
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-892B	98.00	67.11	821
HSA-MIR-146B-3P	97.83	65.29	782
HSA-MIR-493-3P	97.50	66.44	731
HSA-MIR-3121-5P	97.30	66.62	1146
HSA-MIR-12128	96.67	66.98	1471
HSA-MIR-4794	96.47	65.53	1063
HSA-MIR-664A-5P	95.84	64.93	949

Literature-anchored findings (GeneRIF, showing 8)

• Small proline-rich proteins (SPRR2A) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial-mesenchymal transition (EMT) in cholangiocytes. (PMID:18155796)
• Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families. (PMID:18643845)
• SPRR2A functions as a suppressor of p53-dependent transcriptional activity, which otherwise might impede cellular processes needed for epithelial wound repair responses. (PMID:22731250)
• SPRR2A-associated tumor behavior was mimicked by MUC1 shRNA, which induced EMT and, like SPRR2A+ cells, showed reduced metastatic capabilities (PMID:23728799)
• SPRR2a modulates ZEB-1 signaling by way of miR-200c/141-associated epithelial mesenchyme transition through SH3-domain networks and contributes to benign and malignant wound-healing responses. (PMID:24123265)
• Expression of SPRR1 and of SPRR2A is increased in mucosal samples from patients with chronic rhinosinusitis and appeared as a downstream result of TNF alpha modulation, which possibly resulted in epithelial barrier dysfunction. (PMID:28859701)
• Assessment of SPRR2A protein expression in a clinical cohort of patients with head and neck squamous cell carcinoma (HNSCC) confirmed common SPRR2A downregulation in primary tumors and lymph node metastases, but not in normal tissue. High expression of SPRR2A in lymph node metastases was, along with nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence. (PMID:30108165)
• Serum Small Proline-Rich Protein 2A (SPRR2A) Is a Noninvasive Biomarker in Gastric Cancer. (PMID:32908616)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Small proline-rich protein 2A — P35326 (reviewed: P35326)

Alternative names: 2-1

All UniProt accessions (1): P35326

UniProt curated annotations — full annotation on UniProt →

Function. Gut bactericidal protein that selectively kills Gram-positive bacteria by binding to negatively charged lipids on bacterial membranes, leading to bacterial membrane permeabilization and disruption. Specifically binds lipids bearing negatively charged headgroups, such as phosphatidic acid, phosphatidylserine (PS), cardiolipin (CL), and phosphatidylinositol phosphates, but not to zwitterionic or neutral lipids. Induced by type-2 cytokines in response to helminth infection and is required to protect against helminth-induced bacterial invasion of intestinal tissue. May also be involved in the development of the cornified envelope of squamous epithelia; however, additional evidences are required to confirm this result in vivo.

Subcellular location. Secreted. Extracellular space. Cytoplasmic vesicle. Secretory vesicle.

Tissue specificity. Expressed in intestine; selectively expressed in goblet cells.

Post-translational modifications. Forms five pairs of intrachain disulfide bonds.

Induction. During squamous differentiation of epidermal keratinocytes.

Similarity. Belongs to the cornifin (SPRR) family.

RefSeq proteins (1): NP_005979* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029142	SPRR2	Family

Pfam: PF14820

UniProt features (8 total): repeat 3, region of interest 3, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35326-F1	77.32	0.14

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-9725554	Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 82 (showing top): GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOCC_SECRETORY_GRANULE, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_HUMORAL_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_GRAM_POSITIVE_BACTERIUM, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_DEFENSE_RESPONSE_TO_BACTERIUM, KAYO_AGING_MUSCLE_UP, GOCC_SECRETORY_VESICLE, chr1q21

GO Biological Process (4): antibacterial humoral response (GO:0019731), host-mediated modulation of intestinal microbiota composition (GO:0048874), defense response to Gram-positive bacterium (GO:0050830), defense response to bacterium (GO:0042742)

GO Molecular Function (2): lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (7): cornified envelope (GO:0001533), extracellular region (GO:0005576), cytoplasm (GO:0005737), cytosol (GO:0005829), transport vesicle (GO:0030133), secretory granule (GO:0030141), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Developmental Biology	2
Keratinization	1
Developmental Cell Lineages of the Integumentary System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
defense response to bacterium	2
binding	2
cytoplasm	2
endomembrane system	2
antimicrobial humoral response	1
homeostasis of number of cells	1
host-mediated perturbation of symbiont process	1
defense response	1
response to bacterium	1
plasma membrane	1
intracellular anatomical structure	1
cytoplasmic vesicle	1
secretory vesicle	1
intracellular vesicle	1

Protein interactions and networks

STRING

542 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRR2A	ELF3	P78545	817
SPRR2A	SPRR1B	P22528	809
SPRR2A	POU2F3	Q9UKI9	803
SPRR2A	SPRR1A	P35321	801
SPRR2A	SPRR2D	P22532	800
SPRR2A	SPRR2F	Q96RM1	785
SPRR2A	LCE3D	Q9BYE3	780
SPRR2A	LCE3E	Q5T5B0	745
SPRR2A	SPRR2E	P22531	728
SPRR2A	LCE3A	Q5TA76	721
SPRR2A	SPRR3	Q9UBC9	699
SPRR2A	LCE2C	Q5TA81	656
SPRR2A	LCE2D	Q5TA82	656
SPRR2A	LCE1C	Q5T751	621
SPRR2A	C4BPA	P04003	569

IntAct

23 interactions, top by confidence:

A	B	Type	Score
ARL3	UNC119B	psi-mi:“MI:0914”(association)	0.730
SPRR2A	SRC	psi-mi:“MI:0407”(direct interaction)	0.600
SPRR2A	SRC	psi-mi:“MI:0915”(physical association)	0.600
SPRR2A	YES1	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	SPRR2A	psi-mi:“MI:0407”(direct interaction)	0.440
CRK	SPRR2A	psi-mi:“MI:0407”(direct interaction)	0.440
ABL1	SPRR2A	psi-mi:“MI:0407”(direct interaction)	0.440
HCK	SPRR2A	psi-mi:“MI:0407”(direct interaction)	0.440
CTTN	SPRR2A	psi-mi:“MI:0407”(direct interaction)	0.440
SPRR2A	ITK	psi-mi:“MI:0407”(direct interaction)	0.440
Cdk1		psi-mi:“MI:0915”(physical association)	0.400
Retreg2		psi-mi:“MI:0915”(physical association)	0.400
Them6		psi-mi:“MI:0915”(physical association)	0.400
SPRR2A	AKT2	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
OPG065	TUBB8B	psi-mi:“MI:0914”(association)	0.350
WRAP73	SPRR2A	psi-mi:“MI:0915”(physical association)	0.000
SPRR2A	ARL3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Reconstituted Complex), SPRR2A (Affinity Capture-Western), SPRR2A (Affinity Capture-MS), ARL3 (Affinity Capture-MS), SPRR2A (Affinity Capture-MS), SPRR2A (Affinity Capture-MS), SPRR2A (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTR4, A6QNZ4, O14633, O70554, O70555, O70556, O70557, O70558, O70559, O70560, O70562, P15265, P22528, P22531, P22532, P35321, P35322, P35323, P35324, P35325, P35326, P49901, Q28658, Q32L04, Q4KL71, Q4R956, Q5T5B0, Q5T750, Q5T752, Q5T754, Q5T870, Q5T871, Q5TA76, Q5TA77, Q5TA78, Q5TA79, Q5TA81, Q5TA82, Q5TCM9, Q62266

Diamond homologs: O70554, O70555, O70556, O70557, O70558, O70559, O70560, O70562, P22531, P22532, P35325, P35326, Q4KL71, Q96RM1, Q9BYE4, Q9CQK8, O70561

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ELF3	“up-regulates quantity by expression”	SPRR2A	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
FCGR3A-mediated phagocytosis	5	55.1×	7e-06

GO biological processes:

GO term	Partners	Fold	FDR
intracellular signal transduction	5	10.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

246 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153056754:TC:T	acceptor_loss	1.0000
1:153056755:C:CC	acceptor_gain	1.0000
1:153056756:T:G	acceptor_loss	1.0000
1:153056750:AGGAT:A	acceptor_gain	0.9900
1:153056752:GAT:G	acceptor_gain	0.9900
1:153057466:CTCA:C	donor_loss	0.9900
1:153057467:TCA:T	donor_loss	0.9900
1:153057468:CACCA:C	donor_loss	0.9900
1:153057469:A:C	donor_loss	0.9900
1:153056751:GGAT:G	acceptor_gain	0.9800
1:153056753:AT:A	acceptor_gain	0.9800
1:153057465:ACT:A	donor_loss	0.9800
1:153057469:A:AC	donor_gain	0.9800
1:153057470:C:CC	donor_gain	0.9800
1:153056764:A:AC	acceptor_gain	0.9600
1:153057464:GACTC:G	donor_loss	0.9600
1:153056764:A:C	acceptor_gain	0.9500
1:153056748:TCAGG:T	acceptor_gain	0.9400
1:153057470:CCA:C	donor_gain	0.9300
1:153057470:CCAG:C	donor_gain	0.9300
1:153057093:T:C	donor_gain	0.9200
1:153057469:AC:A	donor_gain	0.8800
1:153057470:CC:C	donor_gain	0.8800
1:153057470:CCAGG:C	donor_gain	0.8600
1:153056767:A:C	acceptor_gain	0.8500
1:153057496:TCAGG:T	donor_gain	0.8000
1:153057424:A:C	donor_gain	0.7800
1:153056767:A:AC	acceptor_gain	0.7600
1:153056987:T:A	acceptor_gain	0.7300
1:153057006:T:TC	acceptor_gain	0.7300

AlphaMissense

459 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153056702:A:G	C12R	0.785
1:153056700:G:C	C12W	0.718
1:153056714:A:G	C8R	0.698
1:153056709:C:A	K9N	0.686
1:153056709:C:G	K9N	0.686
1:153056712:G:C	C8W	0.682
1:153056701:C:G	C12S	0.681
1:153056702:A:T	C12S	0.681
1:153056520:C:A	K72N	0.662
1:153056520:C:G	K72N	0.662
1:153056718:C:A	Q6H	0.624
1:153056718:C:G	Q6H	0.624
1:153056715:C:A	Q7H	0.610
1:153056715:C:G	Q7H	0.610
1:153056655:A:C	C27W	0.607
1:153056684:A:G	C18R	0.589
1:153056667:G:C	C23W	0.586
1:153056630:A:G	C36R	0.573
1:153056521:T:A	K72M	0.572

dbSNP variants (sampled 300 via entrez): RS1000992775 (1:153057744 T>A), RS1002332094 (1:153057806 G>A), RS1002491539 (1:153058011 G>C), RS1003615077 (1:153058694 AGT>A), RS1006584973 (1:153056614 C>T), RS1006629063 (1:153055645 C>T), RS1007116402 (1:153057931 T>C), RS1007854841 (1:153059349 A>G), RS1008255842 (1:153057292 A>G), RS1008308173 (1:153056994 A>C), RS1008589203 (1:153058643 A>G), RS1008641355 (1:153058380 G>A), RS1009807994 (1:153057764 G>A), RS1009868851 (1:153059496 C>T), RS1010143279 (1:153059085 T>C)

Disease associations

OMIM: gene MIM:182267 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007564_25	Asthma or allergic disease (pleiotropy)	5.000000e-09
GCST008916_87	Asthma	2.000000e-13
GCST010984_2	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	4.000000e-12
GCST010985_14	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	4.000000e-28

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	3
sodium arsenate	decreases expression, increases abundance, increases expression	2
Arsenic	increases abundance, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
butyraldehyde	increases expression	1
Decitabine	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Allergens	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Coal Tar	increases expression	1
Endosulfan	increases expression	1
Mustard Gas	increases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
beta-Naphthoflavone	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

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