SPA17

Summary

SPA17 (sperm autoantigenic protein 17, HGNC:11210) is a protein-coding gene on chromosome 11q24.2, encoding Sperm surface protein Sp17 (Q15506). Sperm surface zona pellucida binding protein.

This gene encodes a protein present at the cell surface. The N-terminus has sequence similarity to human cAMP-dependent protein kinase A (PKA) type II alpha regulatory subunit (RIIa) while the C-terminus has an IQ calmodulin-binding motif. The central portion of the protein has carbohydrate binding motifs and likely functions in cell-cell adhesion. The protein was initially characterized by its involvement in the binding of sperm to the zona pellucida of the oocyte. Recent studies indicate that it is also involved in additional cell-cell adhesion functions such as immune cell migration and metastasis. A retrotransposed pseudogene is present on chromosome 10q22.

Source: NCBI Gene 53340 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 16 total
• MANE Select transcript: NM_017425

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11210
Approved symbol	SPA17
Name	sperm autoantigenic protein 17
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	SP17, CT22
Ensembl gene	ENSG00000064199
Ensembl biotype	protein_coding
OMIM	608621
Entrez	53340

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000227135, ENST00000524614, ENST00000529498, ENST00000532692, ENST00000889322, ENST00000889323, ENST00000919291, ENST00000919292, ENST00000919293

RefSeq mRNA: 1 — MANE Select: NM_017425 NM_017425

CCDS: CCDS8450

Canonical transcript exons

ENST00000227135 — 5 exons

Exon	Start	End
ENSE00001014300	124673904	124673952
ENSE00002166904	124694303	124697518
ENSE00003490356	124681389	124681459
ENSE00003505881	124675238	124675418
ENSE00003615228	124691696	124691782

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 98.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.0402 / max 531.8351, expressed in 1727 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117380	11.5859	1710
117379	0.3173	121
206484	0.1369	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	98.69	gold quality
sperm	CL:0000019	98.66	gold quality
epithelium of bronchus	UBERON:0002031	98.05	gold quality
left testis	UBERON:0004533	97.95	gold quality
male germ cell	CL:0000015	97.75	gold quality
right testis	UBERON:0004534	97.34	gold quality
bronchus	UBERON:0002185	97.19	gold quality
adult organism	UBERON:0007023	96.61	gold quality
testis	UBERON:0000473	95.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.00	gold quality
right uterine tube	UBERON:0001302	92.42	gold quality
caput epididymis	UBERON:0004358	90.09	gold quality
choroid plexus epithelium	UBERON:0003911	89.18	gold quality
epithelium of nasopharynx	UBERON:0001951	88.22	gold quality
nasal cavity epithelium	UBERON:0005384	86.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.53	gold quality
corpus epididymis	UBERON:0004359	85.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.34	gold quality
ventricular zone	UBERON:0003053	82.08	gold quality
islet of Langerhans	UBERON:0000006	81.95	gold quality
cranial nerve II	UBERON:0000941	81.64	gold quality
nasal cavity mucosa	UBERON:0001826	81.48	gold quality
mucosa of transverse colon	UBERON:0004991	78.85	gold quality
prefrontal cortex	UBERON:0000451	77.79	gold quality
adenohypophysis	UBERON:0002196	77.75	gold quality
pituitary gland	UBERON:0000007	77.29	gold quality
endometrium	UBERON:0001295	77.02	gold quality
right lung	UBERON:0002167	76.05	gold quality
secondary oocyte	CL:0000655	75.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	61.32
E-GEOD-134144	yes	31.21
E-MTAB-10287	yes	27.05
E-HCAD-1	yes	25.60
E-GEOD-130148	yes	13.34
E-ANND-3	yes	10.61
E-MTAB-9388	yes	7.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting SPA17, 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-3134	100.00	66.43	777
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-4260	98.78	65.37	848

Literature-anchored findings (GeneRIF, showing 22)

• Sp17 has different expression patterns in cancer cell lines as compared to normal non-testes tissues and a potential pathogenic role in diseased cells (PMID:12213290)
• focuses on the characterization of the genomic organization of an intron-containing gene and establishes a new transcription model (PMID:12393185)
• expression of Sp17, a thought to be gamete-specific protein, in the synoviocytes of 8/8 female rheumatoid arthritis patients (PMID:12739786)
• identification of a nonapeptide sequence within the Sp17 protein that is predicted to have a high binding affinity for HLA-A1 molecules (PMID:14566839)
• Sp17 is expressed in the cell nucleus of ovarian neoplasms (PMID:14712480)
• Sp17 gene expression in myeloma cells is regulated by promoter methylation (PMID:15381930)
• Overexpression of sperm protein 17 is associated with esophageal cancer (PMID:17230514)
• in vitro cultured, monoclonal, cytotoxic T lymphocytes (derived either from advanced OC patients or from healthy donors), specific for sperm protein 17, can eradicate human metastatic OC cells. (PMID:18779750)
• Results suggest a possible role of Sp17 in regulating sperm maturation, capacitation, acrosomal reaction and interactions with the oocyte zona pellucida during the fertilization process. (PMID:19604394)
• Data show that cisplatin induced decrease in Sp17 levels was due to transcriptional inhibition and cisplatin-resistant cell lines did not show this decrease in Sp17 levels in response to cisplatin treatment. (PMID:19685492)
• HSp17 plays a role in metastatic disease and resistance of epithelial ovarian carcinoma to chemotherapy (PMID:19744347)
• Sperm protein 17 is highly expressed in endometrial and cervical cancers. (PMID:20712874)
• SP17 was expressed in many cancer types with an overall frequency of 12%. SP17 was most frequently expressed in a different set of cancer types than MAGE-A and GAGE antigens and rarely overlapped with these proteins. (PMID:23137323)
• Sp17 is highly expressed in hepatocellular carcinoma cells (PMID:23923079)
• NY-ESO-1 and SP17 was not significantly associated with a specific histotype, but high-level GAGE expression was more frequent in squamous cell carcinoma. GAGE expression was demonstrated to be significantly higher in stage II-IIIa than stage I NSCLC. (PMID:24103781)
• Sp17 and ASP cancer/testis antigens were found in ciliated cells of four ciliated hepatic foregut cysts (CHFCs). Further characterization of Sp17 and ASP in patients with CHFCs may provide significant clues for understanding the molecular mechanisms underlying their predisposition to develop squamous cell carcinomas. (PMID:25600306)
• SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in lung cancer patients. (PMID:25739119)
• dendritic cells from human umbilical cord blood modulated for SP17 expression induced antigen-specific anti-tumor immunity against SP17(+) non-small cell lung cancer. (PMID:26300426)
• Results find that Sp17 is highly expressed in benign, borderline, and low grade malignant serous ovarian neoplasms and can be quantified in serum. Sp17 expression may have diagnostic significance in this subset of patients. (PMID:30309325)
• data suggests that SPA17, ANXA2, and SERPINA5 may potentially serve as non-invasive protein biomarkers associated with the fertilization process of the spermatozoa in unexplained male infertility (PMID:31336797)
• Serum Sp17 Autoantibody Serves as a Potential Specific Biomarker in Patients with SAPHO Syndrome. (PMID:33392854)
• ANXA2, SP17, SERPINA5, PRDX2 genes, and sperm DNA fragmentation differentially represented in male partners of infertile couples with normal and abnormal sperm parameters. (PMID:36177795)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spa17	ENSMUSG00000001948
rattus_norvegicus	Spa17	ENSRNOG00000010934
drosophila_melanogaster	igl	FBGN0013467
caenorhabditis_elegans		WBGENE00018214

Paralogs (2): GAP43 (ENSG00000172020), RIIAD1 (ENSG00000178796)

Protein

Protein identifiers

Sperm surface protein Sp17 — Q15506 (reviewed: Q15506)

Alternative names: Cancer/testis antigen 22, Sp17-1, Sperm autoantigenic protein 17

All UniProt accessions (2): Q15506, A0A172Q397

UniProt curated annotations — full annotation on UniProt →

Function. Sperm surface zona pellucida binding protein. Helps to bind spermatozoa to the zona pellucida with high affinity. Might function in binding zona pellucida and carbohydrates.

Subunit / interactions. Homodimer. May interact with ROPN1.

Subcellular location. Membrane.

Tissue specificity. Testis and sperm specific.

RefSeq proteins (1): NP_059121* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR003117	cAMP_dep_PK_reg_su_I/II_a/b	Domain
IPR012105	Sp17	Family
IPR047579	DD_CABYR_SP17	Domain

Pfam: PF00612, PF02197

UniProt features (5 total): region of interest 2, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8J07	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15506-F1	76.98	0.44

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 188 (showing top): MORF_ITGA2, GOBP_SINGLE_FERTILIZATION, MORF_MSH3, SP3_Q3, MORF_BRCA1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOCC_CELL_SURFACE, GOBP_MALE_GAMETE_GENERATION, GGGTGGRR_PAX4_03, MORF_RAD51L3, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, MODULE_205, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, MORF_CTSB

GO Biological Process (4): epithelial cilium movement involved in extracellular fluid movement (GO:0003351), spermatogenesis (GO:0007283), single fertilization (GO:0007338), binding of sperm to zona pellucida (GO:0007339)

GO Molecular Function (2): calmodulin binding (GO:0005516), protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), cytoplasm (GO:0005737), cilium (GO:0005929), external side of plasma membrane (GO:0009897), motile cilium (GO:0031514), sperm fibrous sheath (GO:0035686), neuron projection (GO:0043005), sperm principal piece (GO:0097228), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
plasma membrane bounded cell projection	2
sperm flagellum	2
cilium movement	1
extracellular transport	1
microtubule-based transport	1
developmental process involved in reproduction	1
male gamete generation	1
fertilization	1
sperm-egg recognition	1
protein binding	1
binding	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane	1
cell surface	1
side of membrane	1
cilium	1

Protein interactions and networks

STRING

1422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPA17	CABYR	O75952	945
SPA17	AKAP3	O75969	936
SPA17	ROPN1	Q9HAT0	927
SPA17	ROPN1L	Q96C74	905
SPA17	ZPBP	Q9BS86	863
SPA17	ABHD2	P08910	829
SPA17	SAGE1	Q9NXZ1	815
SPA17	GAS2L2	Q8NHY3	767
SPA17	RASL10A	Q92737	763
SPA17	PAGE5	Q96GU1	720
SPA17	MAGEC2	Q9UBF1	720
SPA17	PRKAR2A	P13861	711
SPA17	GAS2L1	Q99501	695
SPA17	RHPN1	Q8TCX5	682
SPA17	GAS2	O43903	676

IntAct

47 interactions, top by confidence:

A	B	Type	Score
SPA17	MYL6B	psi-mi:“MI:0915”(physical association)	0.830
MYL6B	SPA17	psi-mi:“MI:0915”(physical association)	0.830
ROPN1	SPA17	psi-mi:“MI:0915”(physical association)	0.810
SPA17	ROPN1	psi-mi:“MI:0915”(physical association)	0.810
ROPN1L	SPA17	psi-mi:“MI:0914”(association)	0.740
SPA17	ROPN1L	psi-mi:“MI:0915”(physical association)	0.740
SPA17	AKAP7	psi-mi:“MI:0915”(physical association)	0.720
AKAP7	SPA17	psi-mi:“MI:0915”(physical association)	0.720
FBXO44	SKP1	psi-mi:“MI:0914”(association)	0.670
ACTN2	SPA17	psi-mi:“MI:0915”(physical association)	0.560
AKAP7	SPA17	psi-mi:“MI:0915”(physical association)	0.550
FBXO44	CUL1	psi-mi:“MI:0914”(association)	0.530
AKAP14	PRKAR2A	psi-mi:“MI:0914”(association)	0.530
SPA17	EFCAB7	psi-mi:“MI:0914”(association)	0.350
AKAP14	EFCAB7	psi-mi:“MI:0914”(association)	0.350
CSAG1	NAP1L4	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): SPA17 (Two-hybrid), ROPN1 (Two-hybrid), MYL6B (Two-hybrid), SPA17 (Affinity Capture-MS), SPA17 (Affinity Capture-MS), SPA17 (Affinity Capture-MS), PRKAR2B (Affinity Capture-MS), MYL6B (Affinity Capture-MS), SEC63 (Affinity Capture-MS), EFCAB7 (Affinity Capture-MS), WDR45B (Affinity Capture-MS), USP33 (Affinity Capture-MS), SPA17 (Affinity Capture-MS), SPA17 (Two-hybrid), SPA17 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GV96, A0MZ66, A0MZ67, A2VDA9, A5PJI6, A6NKN8, A8R4Q8, E7F7X0, O14990, O19021, O42932, O62770, O62771, P13505, P36425, P48539, P54866, P63054, P63055, P84086, P84087, P84088, Q04504, Q0P561, Q148C4, Q15506, Q28IH8, Q3UYG8, Q4R615, Q5F3A1, Q5M8L3, Q5R4Q3, Q5ZM33, Q62252, Q62736, Q6DBA5, Q6GNQ4, Q6NWC9, Q6P3G4, Q6PUV4

Diamond homologs: O19021, O62770, O62771, O75952, P00515, P12368, P13861, P36425, Q15506, Q4R3X7, Q62252, Q710D7, Q95230, Q9D424, A0A509AKL0, A5K0N4, O14448, O42794, O59922, O77676, P00514, P00516, P05207, P05987, P07278, P07802, P09456, P0A2T6, P0A2T7, P0ACJ8, P0ACJ9, P0ACK0, P0ACK1, P0C605, P10644, P12367, P12369, P12849, P16905, P30625

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

666 predictions. Top by Δscore:

Variant	Effect	Δscore
11:124673950:G:GT	donor_gain	1.0000
11:124675415:GAGA:G	donor_gain	1.0000
11:124675417:GA:G	donor_gain	1.0000
11:124675419:G:GG	donor_gain	1.0000
11:124691686:A:AG	acceptor_gain	1.0000
11:124691687:T:G	acceptor_gain	1.0000
11:124691689:T:TA	acceptor_gain	1.0000
11:124691691:TCCA:T	acceptor_loss	1.0000
11:124691694:A:AG	acceptor_gain	1.0000
11:124691694:AG:A	acceptor_gain	1.0000
11:124691694:AGG:A	acceptor_loss	1.0000
11:124691695:G:GG	acceptor_gain	1.0000
11:124691695:G:GT	acceptor_loss	1.0000
11:124691695:GG:G	acceptor_gain	1.0000
11:124691695:GGA:G	acceptor_gain	1.0000
11:124691695:GGAGC:G	acceptor_gain	1.0000
11:124691759:G:GT	donor_gain	1.0000
11:124691778:TCTTA:T	donor_gain	1.0000
11:124691781:TA:T	donor_gain	1.0000
11:124691783:G:GG	donor_gain	1.0000
11:124673949:GGAG:G	donor_gain	0.9900
11:124673950:GAGG:G	donor_loss	0.9900
11:124673951:AGG:A	donor_loss	0.9900
11:124673953:G:GA	donor_loss	0.9900
11:124673954:T:A	donor_loss	0.9900
11:124675416:A:T	donor_gain	0.9900
11:124675601:A:AG	acceptor_gain	0.9900
11:124675602:T:G	acceptor_gain	0.9900
11:124691693:CAGG:C	acceptor_gain	0.9900
11:124691694:AGGA:A	acceptor_gain	0.9900

AlphaMissense

1009 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:124675376:T:C	F38L	0.997
11:124675378:T:A	F38L	0.997
11:124675378:T:G	F38L	0.997
11:124675347:T:C	L28P	0.996
11:124675382:G:C	A40P	0.996
11:124694357:G:C	A123P	0.996
11:124675323:T:A	L20H	0.995
11:124675332:T:C	L23P	0.995
11:124675338:G:C	R25P	0.995
11:124675380:C:A	A39E	0.994
11:124675307:G:A	G15R	0.993
11:124675307:G:C	G15R	0.993
11:124675358:C:T	P32S	0.993
11:124675359:C:A	P32Q	0.993
11:124675368:T:A	I35K	0.993
11:124675379:G:C	A39P	0.993
11:124675414:A:C	R50S	0.993
11:124675414:A:T	R50S	0.993
11:124675401:T:C	L46P	0.992
11:124675302:C:A	P13Q	0.990
11:124675320:T:C	L19P	0.990
11:124675368:T:G	I35R	0.990
11:124694367:G:C	R126P	0.990
11:124675311:T:C	F16S	0.989
11:124675323:T:C	L20P	0.989
11:124675388:T:G	Y42D	0.989
11:124694352:T:C	I121T	0.989
11:124675332:T:A	L23Q	0.988
11:124675377:T:C	F38S	0.988
11:124675391:T:C	F43L	0.988

dbSNP variants (sampled 300 via entrez): RS1000162551 (11:124683734 C>A,T), RS1000215927 (11:124675064 T>G), RS1000272722 (11:124674841 A>T), RS1000297954 (11:124683468 A>C,G), RS1000318835 (11:124688662 A>C), RS1000781082 (11:124682011 G>A), RS1001275698 (11:124673213 C>A), RS1001433754 (11:124694523 T>C), RS1001441458 (11:124687733 C>T), RS1001686527 (11:124675529 G>A), RS1002033360 (11:124692796 G>C), RS1002228744 (11:124675137 G>A), RS1002312429 (11:124680336 C>T), RS1002442365 (11:124678380 G>C), RS1002447472 (11:124686168 G>A,C)

Disease associations

OMIM: gene MIM:608621 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006865_13	Bipolar disorder	6.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	5
sodium arsenite	increases abundance, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
Cyclosporine	affects expression, decreases expression	2
Particulate Matter	increases abundance, affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Leflunomide	decreases expression	1
Arsenic	increases abundance, increases expression	1
Doxorubicin	decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Manganese	decreases expression	1
Phenobarbital	affects expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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