ADGRA1

Summary

ADGRA1 (adhesion G protein-coupled receptor A1, HGNC:13838) is a protein-coding gene on chromosome 10q26.3, encoding Adhesion G protein-coupled receptor A1 (Q86SQ6). Orphan receptor.

This gene encodes a protein that belongs to the adhesion family of G-protein-coupled receptors. Members of this family function in several sensory systems and regulate blood pressure, immune responses, food intake and development. A similar protein in rodents is thought to play a role in in the regulation of neuronal signaling pathways. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.

Source: NCBI Gene 84435 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 124 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001083909

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13838
Approved symbol	ADGRA1
Name	adhesion G protein-coupled receptor A1
Location	10q26.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1828
Ensembl gene	ENSG00000197177
Ensembl biotype	protein_coding
OMIM	612302
Entrez	84435

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000392606, ENST00000392607, ENST00000864054

RefSeq mRNA: 2 — MANE Select: NM_001083909 NM_001083909, NM_001291085

CCDS: CCDS41580, CCDS76362

Canonical transcript exons

ENST00000392607 — 7 exons

Exon	Start	End
ENSE00001512487	133087924	133088138
ENSE00001622464	133096974	133097101
ENSE00001680963	133098640	133098763
ENSE00001931650	133128329	133131675
ENSE00002209139	133088708	133088912
ENSE00002494549	133127233	133127331
ENSE00003514083	133102697	133102842

Expression profiles

Bgee: expression breadth broad, 94 present calls, max score 87.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8990 / max 41.5640, expressed in 168 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107745	0.6984	150
107746	0.1045	56
107747	0.0389	25
107744	0.0339	21
107743	0.0234	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	87.87	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.62	gold quality
anterior cingulate cortex	UBERON:0009835	86.44	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.82	gold quality
prefrontal cortex	UBERON:0000451	85.09	gold quality
hypothalamus	UBERON:0001898	83.70	gold quality
neocortex	UBERON:0001950	83.37	gold quality
lateral nuclear group of thalamus	UBERON:0002736	83.32	gold quality
frontal cortex	UBERON:0001870	83.18	gold quality
primary visual cortex	UBERON:0002436	82.14	gold quality
cerebral cortex	UBERON:0000956	81.74	gold quality
amygdala	UBERON:0001876	80.75	gold quality
ventricular zone	UBERON:0003053	79.32	gold quality
middle temporal gyrus	UBERON:0002771	79.05	gold quality
ganglionic eminence	UBERON:0004023	78.61	gold quality
Ammon’s horn	UBERON:0001954	77.89	gold quality
forebrain	UBERON:0001890	76.36	gold quality
occipital lobe	UBERON:0002021	76.18	gold quality
temporal lobe	UBERON:0001871	76.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.52	gold quality
pancreatic ductal cell	CL:0002079	74.87	silver quality
brain	UBERON:0000955	74.74	gold quality
superior frontal gyrus	UBERON:0002661	73.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	73.26	gold quality
substantia nigra	UBERON:0002038	72.57	gold quality
spinal cord	UBERON:0002240	72.56	gold quality
Brodmann (1909) area 46	UBERON:0006483	71.92	gold quality
nucleus accumbens	UBERON:0001882	71.05	gold quality
caudate nucleus	UBERON:0001873	71.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting ADGRA1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4688	99.48	64.68	828

Literature-anchored findings (GeneRIF, showing 3)

• Studies indicate that the orthologs of GP123 in mouse and rat play a role in the regulation of neuronal signaling pathways. (PMID:17212699)
• Adhesion GPR123 is an indicator for recurrence and prognosis in bladder cancer. (PMID:33945147)
• Essential Role of Adhesion GPCR, GPR123, for Human Pluripotent Stem Cells and Reprogramming towards Pluripotency. (PMID:36672239)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Adgra1	ENSMUSG00000025475
rattus_norvegicus	Adgra1	ENSRNOG00000054955

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), CALCRL (ENSG00000064989), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADGRL1 (ENSG00000072071), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), GHRHR (ENSG00000106128), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE5 (ENSG00000123146), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), PTH2R (ENSG00000144407), ADGRG7 (ENSG00000144820), ADGRL3 (ENSG00000150471), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885)

Protein

Protein identifiers

Adhesion G protein-coupled receptor A1 — Q86SQ6 (reviewed: Q86SQ6)

Alternative names: G-protein coupled receptor 123

All UniProt accessions (1): Q86SQ6

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor.

Subcellular location. Membrane.

Similarity. Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86SQ6-3	3	yes
Q86SQ6-1	1
Q86SQ6-2	2

RefSeq proteins (2): NP_001077378, NP_001278014 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000832	GPCR_2_secretin-like	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR051963	Adhesion_GPCR_A	Family

Pfam: PF00002

UniProt features (30 total): topological domain 8, transmembrane region 7, region of interest 3, compositionally biased region 3, splice variant 3, sequence variant 3, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86SQ6-F1	64.30	0.30

Functional residue map

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

Glycosylation sites (1): 75

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 49 (showing top): SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOCC_POSTSYNAPSE, GOCC_SYNAPSE, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, GOBP_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOCC_GLUTAMATERGIC_SYNAPSE, GOCC_NEURON_TO_NEURON_SYNAPSE, MIR6867_5P, MIR5010_3P, MIR4731_5P, MIR6722_3P, MIR5589_3P, MIR190A_5P, MIR1909_3P

GO Biological Process (3): signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (2): G protein-coupled receptor activity (GO:0004930), transmembrane signaling receptor activity (GO:0004888)

GO Cellular Component (4): plasma membrane (GO:0005886), postsynaptic density (GO:0014069), membrane (GO:0016020), glutamatergic synapse (GO:0098978)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
signaling receptor activity	1
membrane	1
cell periphery	1
asymmetric synapse	1
postsynaptic specialization	1
cellular anatomical structure	1
synapse	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRA1	SCTR	P47872	817
ADGRA1	KNDC1	Q76NI1	665
ADGRA1	ADGRG5	Q8IZF4	639
ADGRA1	ADGRF2P	Q8IZF7	615
ADGRA1	ADGRG3	Q86Y34	612
ADGRA1	ADGRG7	Q96K78	603
ADGRA1	ADGRD2	Q7Z7M1	595
ADGRA1	ADGRF1	Q5T601	584
ADGRA1	ADGRF3	Q8IZF5	573
ADGRA1	ADGRF4	Q8IZF3	566
ADGRA1	ADGRG1	Q9Y653	559
ADGRA1	ADGRF5	Q8IZF2	542
ADGRA1	GPR68	Q15743	530
ADGRA1	CDH24	Q86UP0	518
ADGRA1	GPR162	Q16538	510

IntAct

125 interactions, top by confidence:

A	B	Type	Score
DLG1	ADGRA1	psi-mi:“MI:0915”(physical association)	0.610
ADGRA1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.610
ADGRA1	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
ADGRA1	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (1): GPR123 (Positive Genetic)

ESM2 similar proteins: A0A2R9YJI3, A3KFU9, A6QLU6, B2ZHY2, B4XF06, D3Z7H4, D3ZK93, D4A6L0, E1BBQ2, O43194, O75204, P51810, P70259, P82352, Q14714, Q16538, Q17QQ5, Q2T9K0, Q3UN16, Q49LS8, Q4V922, Q5E9H8, Q5MNU5, Q5T848, Q5U431, Q62147, Q6NV75, Q6PI62, Q6UXU4, Q7RTS5, Q7TQN9, Q80ZU9, Q86SQ6, Q8BGE9, Q8BGP5, Q8C419, Q8C4G9, Q8K0Z9, Q8NBV4, Q8VHW3

Diamond homologs: E7FBY6, Q7TT36, Q86SQ6, Q8C4G9, Q8IWK6, Q91ZV8, Q96PE1, S4X0Q8, P48960, Q9BY15, G5EFX6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Ras activation upon Ca2+ influx through NMDA receptor	5	56.0×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	53.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	53.3×	1e-06
Long-term potentiation	5	46.6×	2e-06
Assembly and cell surface presentation of NMDA receptors	8	39.8×	2e-09
Neurexins and neuroligins	9	34.8×	6e-10
Protein-protein interactions at synapses	5	26.0×	3e-05
RHOA GTPase cycle	5	7.3×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	75.5×	2e-14
protein localization to synapse	6	59.7×	9e-08
receptor clustering	7	56.7×	7e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	38.6×	8e-07
cell-cell adhesion	10	13.2×	4e-07
protein-containing complex assembly	8	11.8×	2e-05
regulation of small GTPase mediated signal transduction	5	9.3×	4e-03
protein localization to plasma membrane	6	8.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	112
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3061841	GRCh38/hg38 10q26.2-26.3(chr10:125976998-133427130)x1	Pathogenic

SpliceAI

1825 predictions. Top by Δscore:

Variant	Effect	Δscore
10:133088910:ATGG:A	donor_loss	1.0000
10:133088911:TGGTG:T	donor_loss	1.0000
10:133088913:G:GG	donor_gain	1.0000
10:133088913:GTG:G	donor_loss	1.0000
10:133097099:GAG:G	donor_gain	1.0000
10:133097099:GAGG:G	donor_loss	1.0000
10:133097101:GGTG:G	donor_loss	1.0000
10:133097103:T:G	donor_loss	1.0000
10:133098630:C:CA	acceptor_gain	1.0000
10:133098636:ACAGC:A	acceptor_gain	1.0000
10:133098637:C:G	acceptor_gain	1.0000
10:133098637:CA:C	acceptor_loss	1.0000
10:133098638:A:AC	acceptor_loss	1.0000
10:133098638:A:AG	acceptor_gain	1.0000
10:133098638:AGC:A	acceptor_gain	1.0000
10:133098639:G:A	acceptor_loss	1.0000
10:133098639:G:GA	acceptor_gain	1.0000
10:133098639:GC:G	acceptor_gain	1.0000
10:133098639:GCG:G	acceptor_gain	1.0000
10:133098639:GCGC:G	acceptor_gain	1.0000
10:133098639:GCGCC:G	acceptor_gain	1.0000
10:133098761:GCG:G	donor_gain	1.0000
10:133127327:GCGTA:G	donor_gain	1.0000
10:133127329:GTA:G	donor_gain	1.0000
10:133127332:G:GG	donor_gain	1.0000
10:133128323:CCACA:C	acceptor_loss	1.0000
10:133128324:CACA:C	acceptor_loss	1.0000
10:133128326:CAGC:C	acceptor_loss	1.0000
10:133128327:A:AG	acceptor_gain	1.0000
10:133128327:A:AT	acceptor_loss	1.0000

AlphaMissense

3616 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:133128723:G:A	G299R	0.994
10:133128723:G:C	G299R	0.994
10:133128756:C:A	R310S	0.994
10:133128636:T:A	W270R	0.992
10:133128636:T:C	W270R	0.992
10:133097061:T:C	C31R	0.991
10:133128757:G:C	R310P	0.990
10:133102739:T:A	W100R	0.989
10:133102739:T:C	W100R	0.989
10:133128351:A:C	S175R	0.989
10:133128353:C:A	S175R	0.989
10:133128353:C:G	S175R	0.989
10:133128690:A:C	S288R	0.989
10:133128692:C:A	S288R	0.989
10:133128692:C:G	S288R	0.989
10:133128762:G:C	D312H	0.989
10:133128703:G:A	G292D	0.987
10:133128724:G:A	G299E	0.986
10:133128763:A:C	D312A	0.986
10:133128763:A:T	D312V	0.985
10:133128646:G:A	G273E	0.984
10:133127283:C:A	A151D	0.983
10:133128702:G:C	G292R	0.983
10:133128645:G:T	G273W	0.982
10:133129490:G:C	W554C	0.982
10:133129490:G:T	W554C	0.982
10:133098716:T:C	F70L	0.981
10:133098718:C:A	F70L	0.981
10:133098718:C:G	F70L	0.981
10:133128332:C:G	C168W	0.981

dbSNP variants (sampled 300 via entrez): RS1000006828 (10:133107282 T>C), RS1000020339 (10:133129964 G>A,T), RS1000038962 (10:133118591 G>A,T), RS1000087381 (10:133103909 G>T), RS1000100230 (10:133114241 G>A), RS1000119936 (10:133104042 G>A,T), RS1000209338 (10:133115878 C>T), RS1000247223 (10:133095235 A>G), RS1000430373 (10:133114034 C>T), RS1000436387 (10:133100023 T>C), RS1000443095 (10:133107541 T>C), RS1000574950 (10:133112245 T>C), RS1000579786 (10:133087796 C>T), RS1000652578 (10:133108033 G>A), RS1000677929 (10:133122723 T>C)

Disease associations

OMIM: gene MIM:612302 | disease phenotypes: MIM:617330, MIM:126800

GenCC curated gene-disease

Mondo (2): hypotonia, ataxia, and delayed development syndrome (MONDO:0015021), Duane syndrome type 1 (MONDO:0024265)

Orphanet (2): Duane retraction syndrome (Orphanet:233), Developmental delay-ataxia-hypotonia-facial dysmorphism syndrome (Orphanet:658843)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003264_771	Post bronchodilator FEV1/FVC ratio	3.000000e-07
GCST008369_14	Plasma anti-thyroglobulin levels	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523885 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Adhesion Class GPCRs

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
bisphenol A	decreases methylation	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, affects methylation	1
Arsenic	affects methylation	1
Vehicle Emissions	affects methylation, increases abundance	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
S-Nitrosoglutathione	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883404	Binding	PRESTO-Tango GPCRome screening (GPR123)	Data for DCP probe UCSF924

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KX28	PathHunter CHO-K1 GPR123 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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