SYNPO2L

Summary

SYNPO2L (synaptopodin 2 like, HGNC:23532) is a protein-coding gene on chromosome 10q22.2, encoding Synaptopodin 2-like protein (Q9H987). Actin-associated protein that may play a role in modulating actin-based shape.

Predicted to enable actin binding activity. Predicted to be involved in several processes, including positive regulation of Rho protein signal transduction; positive regulation of stress fiber assembly; and sarcomere organization. Predicted to be located in cytoplasm and cytoskeleton. Predicted to be active in Z disc; actin cytoskeleton; and nucleus.

Source: NCBI Gene 79933 — RefSeq curated summary.

At a glance

• GWAS associations: 25
• Clinical variants (ClinVar): 141 total
• MANE Select transcript: NM_001114133

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23532
Approved symbol	SYNPO2L
Name	synaptopodin 2 like
Location	10q22.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12921
Ensembl gene	ENSG00000166317
Ensembl biotype	protein_coding
Entrez	79933

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000372873, ENST00000394810, ENST00000606523

RefSeq mRNA: 2 — MANE Select: NM_001114133 NM_001114133, NM_024875

CCDS: CCDS44438, CCDS7331

Canonical transcript exons

ENST00000394810 — 4 exons

Exon	Start	End
ENSE00001458860	73653139	73653653
ENSE00001458861	73654129	73654280
ENSE00001519656	73655818	73656029
ENSE00003847269	73644886	73648879

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 98.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5287 / max 236.8828, expressed in 158 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110099	0.7774	78
110094	0.4361	98
110101	0.2519	43
110096	0.0174	8
110095	0.0169	10
110100	0.0155	12
110102	0.0135	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.87	gold quality
apex of heart	UBERON:0002098	98.85	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.42	gold quality
biceps brachii	UBERON:0001507	98.40	gold quality
vastus lateralis	UBERON:0001379	98.04	gold quality
heart right ventricle	UBERON:0002080	97.92	gold quality
myocardium	UBERON:0002349	97.79	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.75	gold quality
left ventricle myocardium	UBERON:0006566	97.65	gold quality
quadriceps femoris	UBERON:0001377	97.61	gold quality
gluteal muscle	UBERON:0002000	97.50	gold quality
skeletal muscle tissue	UBERON:0001134	97.07	gold quality
body of tongue	UBERON:0011876	96.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.95	gold quality
cardiac atrium	UBERON:0002081	96.93	gold quality
cardiac ventricle	UBERON:0002082	96.90	gold quality
heart left ventricle	UBERON:0002084	96.85	gold quality
right atrium auricular region	UBERON:0006631	96.75	gold quality
gastrocnemius	UBERON:0001388	96.51	gold quality
vena cava	UBERON:0004087	96.33	gold quality
deltoid	UBERON:0001476	95.90	gold quality
muscle organ	UBERON:0001630	95.75	gold quality
tibialis anterior	UBERON:0001385	95.07	gold quality
muscle of leg	UBERON:0001383	95.04	gold quality
triceps brachii	UBERON:0001509	94.87	gold quality
muscle tissue	UBERON:0002385	93.61	gold quality
heart	UBERON:0000948	92.58	gold quality
tongue	UBERON:0001723	89.88	gold quality
lower esophagus mucosa	UBERON:0035834	87.19	gold quality
superior surface of tongue	UBERON:0007371	85.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting SYNPO2L, 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-8485	100.00	77.57	4731
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4516	99.61	67.78	3390

Literature-anchored findings (GeneRIF, showing 2)

• we did not observe associations between coding genetic variants and Atrial fibrillation (AF), suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF (PMID:27589061)
• METTL16 Promotes Stability of SYNPO2L mRNA and leading to Cancer Cell Lung Metastasis by Secretion of COL10A1 and attract the Cancer-Associated Fibroblasts. (PMID:39247832)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	synpo2la	ENSDARG00000077293
danio_rerio	synpo2lb	ENSDARG00000078696
mus_musculus	Synpo2l	ENSMUSG00000039376
rattus_norvegicus	Synpo2l	ENSRNOG00000008949
drosophila_melanogaster	CG1674	FBGN0039897

Paralogs (2): SYNPO (ENSG00000171992), SYNPO2 (ENSG00000172403)

Protein

Protein identifiers

Synaptopodin 2-like protein — Q9H987 (reviewed: Q9H987)

All UniProt accessions (2): Q9H987, U3KQD0

UniProt curated annotations — full annotation on UniProt →

Function. Actin-associated protein that may play a role in modulating actin-based shape.

Subcellular location. Cytoplasm. Cytoskeleton.

Similarity. Belongs to the synaptopodin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H987-1	1	yes
Q9H987-2	2

RefSeq proteins (2): NP_001107605, NP_079151 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR051976	Synaptopodin_domain	Family

Pfam: PF00595

UniProt features (59 total): modified residue 34, compositionally biased region 12, region of interest 5, sequence variant 3, splice variant 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H987-F1	53.10	0.12

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 (34): 108, 111, 141, 143, 178, 180, 345, 350, 374, 381, 384, 386, 466, 469, 479, 670, 678, 705, 713, 757 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 143 (showing top): GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, MYOGENIN_Q6, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, MEF2_02, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_SARCOMERE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GNF2_MYL3, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (5): heart morphogenesis (GO:0003007), positive regulation of actin filament bundle assembly (GO:0032233), positive regulation of Rho protein signal transduction (GO:0035025), sarcomere organization (GO:0045214), positive regulation of stress fiber assembly (GO:0051496)

GO Molecular Function (2): actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), organelle (GO:0043226)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
heart development	1
animal organ morphogenesis	1
regulation of actin filament bundle assembly	1
positive regulation of cellular component biogenesis	1
actin filament bundle assembly	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
myofibril assembly	1
actomyosin structure organization	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
cytoskeletal protein binding	1
binding	1
intracellular membrane-bounded organelle	1
cytoskeleton	1
I band	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

858 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYNPO2L	ZFHX3	Q15911	692
SYNPO2L	MYOZ1	Q9NP98	677
SYNPO2L	AOPEP	Q8N6M6	608
SYNPO2L	SYNE2	Q8WXH0	581
SYNPO2L	CAND2	O75155	581
SYNPO2L	TBX3	O15119	568
SYNPO2L	HCN4	Q9Y3Q4	530
SYNPO2L	PRRX1	P54821	512
SYNPO2L	WDTC1	Q8N5D0	485
SYNPO2L	PITX2	Q99697	479
SYNPO2L	KCNN3	Q9UGI6	476
SYNPO2L	NEURL1	O76050	471
SYNPO2L	RPL3L	Q92901	434
SYNPO2L	WNT8A	Q9H1J5	419
SYNPO2L	CCDC197	Q8NCU1	400

IntAct

30 interactions, top by confidence:

A	B	Type	Score
E	SYNPO2L	psi-mi:“MI:0915”(physical association)	0.590
ABCC4	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF16	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
ASIC3	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B4	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
CYSLTR2	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
DGKK	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
FZD7	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
E6	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
ORF putative E6	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
SYNPO2L	E6	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA5	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
KIR3DL3	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
MAP2K2	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
PBK	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
RALBP1	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
RASSF6	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
SLCO1C1	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
TJP2	SYNPO2L	psi-mi:“MI:0407”(direct interaction)	0.440
SYNPO2L	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
SYNPO2L	TOMM20	psi-mi:“MI:0915”(physical association)	0.400
TBC1D2B	CEP120	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): SYNPO2L (Two-hybrid), SYNPO2L (Two-hybrid), SYNPO2L (Two-hybrid), SYNPO2L (Two-hybrid), SYNPO2L (Two-hybrid), GOLGA2 (Two-hybrid), ACTN3 (Two-hybrid), SYNPO2L (Proximity Label-MS), SYNPO2L (Affinity Capture-MS), SYNPO2L (Protein-peptide), SYNPO2L (Cross-Linking-MS (XL-MS)), SYNPO2L (Protein-peptide)

ESM2 similar proteins: D3ZQL6, D4A702, E7F568, E9Q0S6, O35867, O54916, O54931, P19973, Q08495, Q08DM1, Q09YM8, Q1LVV0, Q2MJV9, Q3UH68, Q3UIL6, Q4KM62, Q4PS85, Q5NBX1, Q5R4B6, Q5RBH3, Q5RG44, Q5RHU7, Q5U301, Q68CZ2, Q6P4R8, Q6PIJ4, Q80Z38, Q8BWB1, Q8C5R2, Q8CC35, Q8IVT2, Q8K382, Q8N3V7, Q91YE8, Q96D71, Q9D067, Q9D279, Q9GLM4, Q9H987, Q9HBL0

Diamond homologs: A1ZA47, A2ALU4, A5H447, D4A702, E1BKA3, O00151, O14639, O43294, O60711, O70209, O70400, O75112, O94929, P20271, P48059, P49023, P49024, P50464, P52944, Q09476, Q0WSN2, Q13796, Q15942, Q1JQB5, Q2KJ33, Q2TCH4, Q2YDK0, Q3MHZ4, Q3SX26, Q3SX40, Q3SYZ8, Q3T0X8, Q3TJD7, Q55BI0, Q5F464, Q5R7I1, Q5RCF7, Q5TD97, Q5U2Z2, Q5XI07

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	137
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1043 predictions. Top by Δscore:

Variant	Effect	Δscore
10:73654128:CCG:C	donor_gain	1.0000
10:73648880:C:CC	acceptor_gain	0.9900
10:73653138:CTGG:C	donor_gain	0.9900
10:73654155:T:TA	donor_gain	0.9900
10:73654286:A:AC	acceptor_gain	0.9900
10:73654286:A:C	acceptor_gain	0.9900
10:73648875:CAGTT:C	acceptor_gain	0.9800
10:73648878:TTCTG:T	acceptor_loss	0.9800
10:73648879:TCTGG:T	acceptor_loss	0.9800
10:73648880:C:CA	acceptor_loss	0.9800
10:73648881:T:A	acceptor_loss	0.9800
10:73655813:CTTAC:C	donor_loss	0.9800
10:73655814:TTAC:T	donor_loss	0.9800
10:73655816:A:T	donor_loss	0.9800
10:73655817:CCT:C	donor_loss	0.9800
10:73655929:G:C	donor_gain	0.9800
10:73648877:GTT:G	acceptor_gain	0.9700
10:73650673:A:AC	donor_gain	0.9700
10:73650674:C:CC	donor_gain	0.9700
10:73650674:CACA:C	donor_gain	0.9700
10:73653137:A:AC	donor_gain	0.9700
10:73653138:C:CC	donor_gain	0.9700
10:73653316:CACGG:C	donor_gain	0.9700
10:73654127:A:AC	donor_gain	0.9700
10:73654128:C:CC	donor_gain	0.9700
10:73654280:TC:T	acceptor_loss	0.9700
10:73654281:C:CG	acceptor_loss	0.9700
10:73654282:T:G	acceptor_loss	0.9700
10:73654289:T:C	acceptor_gain	0.9700
10:73654289:T:TC	acceptor_gain	0.9700

AlphaMissense

6176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:73648758:A:C	F298L	1.000
10:73648758:A:T	F298L	1.000
10:73648759:A:G	F298S	1.000
10:73648760:A:G	F298L	1.000
10:73648759:A:C	F298C	0.999
10:73648801:A:G	L284P	0.999
10:73648801:A:T	L284H	0.999
10:73648804:A:G	L283P	0.999
10:73648813:A:T	I280N	0.999
10:73655867:A:G	F19S	0.999
10:73648747:C:G	R302P	0.998
10:73648760:A:C	F298V	0.998
10:73648760:A:T	F298I	0.998
10:73648772:C:G	G294R	0.998
10:73648772:C:T	G294R	0.998
10:73648813:A:C	I280S	0.998
10:73647257:A:G	W799R	0.997
10:73647257:A:T	W799R	0.997
10:73648740:T:A	R304S	0.997
10:73648740:T:G	R304S	0.997
10:73648765:A:G	L296P	0.997
10:73648773:T:A	K293N	0.997
10:73648773:T:G	K293N	0.997
10:73648811:C:G	A281P	0.997
10:73654246:A:G	L47P	0.997
10:73655866:G:C	F19L	0.997
10:73655866:G:T	F19L	0.997
10:73655868:A:G	F19L	0.997
10:73655874:A:G	W17R	0.997
10:73655874:A:T	W17R	0.997

dbSNP variants (sampled 300 via entrez): RS1000261009 (10:73648745 G>A), RS1000630062 (10:73646854 G>T), RS1000878347 (10:73656242 A>T), RS1001060689 (10:73653757 G>A), RS1001377793 (10:73652434 C>T), RS1001407150 (10:73651949 C>T), RS1001483278 (10:73651286 G>A), RS1002214390 (10:73650695 T>A), RS1002535213 (10:73652494 C>T), RS1002545069 (10:73652177 G>A), RS1002770334 (10:73657003 G>A), RS1002941839 (10:73657339 A>G,T), RS1003801727 (10:73647073 G>A,T), RS1003989254 (10:73649664 C>A,G), RS1004004429 (10:73656010 C>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST001499_8	Atrial fibrillation	4.000000e-09
GCST004297_16	Atrial fibrillation	8.000000e-11
GCST004300_3	Incident atrial fibrillation	3.000000e-08
GCST005306_1	Atrial fibrillation	2.000000e-06
GCST006061_29	Atrial fibrillation	6.000000e-27
GCST006061_96	Atrial fibrillation	6.000000e-27
GCST006231_39	Mean arterial pressure	6.000000e-06
GCST006259_61	Systolic blood pressure	8.000000e-09
GCST006414_1	Atrial fibrillation	9.000000e-35
GCST007656_13	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	2.000000e-10
GCST009541_9	Heart failure	1.000000e-09
GCST010321_125	PR interval	3.000000e-19
GCST010796_1565	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-27
GCST010796_1566	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-12
GCST010796_1567	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-14
GCST010796_1568	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-17
GCST010796_1569	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-19
GCST010796_1570	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-20
GCST010796_1571	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-20
GCST010796_1572	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-22
GCST010796_1573	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-22
GCST010796_1574	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-23
GCST010796_1575	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-25
GCST011205_16	Hypertrophic cardiomyopathy (MTAG)	5.000000e-11
GCST011211_11	Hypertrophic cardiomyopathy	3.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006340	mean arterial pressure
EFO:0006335	systolic blood pressure
EFO:0004462	PR interval
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Testosterone	increases expression, decreases expression, affects cotreatment	2
Valproic Acid	increases methylation, increases expression	2
aristolochic acid I	increases expression	1
arsenite	affects expression	1
CGP 52608	increases reaction, affects binding	1
abrine	increases expression	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Doxorubicin	affects expression	1
Naled	affects expression	1
Progesterone	increases expression	1
Triclosan	decreases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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