SPIN4

Summary

SPIN4 (spindlin family member 4, HGNC:27040) is a protein-coding gene on chromosome Xq11.1, encoding Spindlin-4 (Q56A73). Binds to acetylated and methylated histones, including H3K4me3 and H4K20me3, probably acting as a histone reader that recognizes chromatin marks and mediates downstream cellular effects.

Enables methylated histone binding activity. Involved in negative regulation of cell population proliferation and positive regulation of canonical Wnt signaling pathway. Located in chromatin; cytoplasm; and nucleus.

Source: NCBI Gene 139886 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Lui-Jee-Baron syndrome (Moderate, GenCC)
• Clinical variants (ClinVar): 12 total — 1 pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• MANE Select transcript: NM_001012968

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27040
Approved symbol	SPIN4
Name	spindlin family member 4
Location	Xq11.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ44984, TDRD28
Ensembl gene	ENSG00000186767
Ensembl biotype	protein_coding
OMIM	301113
Entrez	139886

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000374884

RefSeq mRNA: 1 — MANE Select: NM_001012968 NM_001012968

CCDS: CCDS43964

Canonical transcript exons

ENST00000374884 — 1 exons

Exon	Start	End
ENSE00001465015	63347228	63351332

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 96.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.8884 / max 209.7798, expressed in 1638 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199442	12.9414	1586
199443	1.1905	698
199441	0.3709	206
199440	0.3304	177
199439	0.0552	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.59	silver quality
esophagus squamous epithelium	UBERON:0006920	92.53	gold quality
epithelial cell of pancreas	CL:0000083	88.74	silver quality
epithelium of nasopharynx	UBERON:0001951	87.64	gold quality
visceral pleura	UBERON:0002401	87.58	gold quality
gingival epithelium	UBERON:0001949	87.42	gold quality
gingiva	UBERON:0001828	85.68	gold quality
oral cavity	UBERON:0000167	85.44	gold quality
trabecular bone tissue	UBERON:0002483	84.83	gold quality
oviduct epithelium	UBERON:0004804	84.58	gold quality
germinal epithelium of ovary	UBERON:0001304	84.17	gold quality
epithelium of mammary gland	UBERON:0003244	83.98	gold quality
mammary duct	UBERON:0001765	83.93	gold quality
ventricular zone	UBERON:0003053	82.88	gold quality
parietal pleura	UBERON:0002400	82.70	gold quality
ganglionic eminence	UBERON:0004023	82.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	82.18	gold quality
bone marrow	UBERON:0002371	81.09	gold quality
lower lobe of lung	UBERON:0008949	80.78	gold quality
colonic mucosa	UBERON:0000317	80.71	gold quality
tibia	UBERON:0000979	80.51	gold quality
palpebral conjunctiva	UBERON:0001812	79.95	gold quality
endometrium	UBERON:0001295	79.37	gold quality
Brodmann (1909) area 23	UBERON:0013554	78.42	gold quality
amniotic fluid	UBERON:0000173	78.30	gold quality
ileal mucosa	UBERON:0000331	78.14	gold quality
placenta	UBERON:0001987	78.09	gold quality
mammary gland	UBERON:0001911	78.05	gold quality
thoracic mammary gland	UBERON:0005200	78.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	77.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

137 targeting SPIN4, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4533	100.00	69.48	2758
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-2110	99.96	66.68	1930

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	spinb	ENSDARG00000035697
danio_rerio	spina	ENSDARG00000058949
mus_musculus	Spin4	ENSMUSG00000071722
rattus_norvegicus	Spin4	ENSRNOG00000077287

Paralogs (4): SPIN1 (ENSG00000106723), SPIN2A (ENSG00000147059), SPIN2B (ENSG00000186787), SPIN3 (ENSG00000204271)

Protein

Protein identifiers

Spindlin-4 — Q56A73 (reviewed: Q56A73)

All UniProt accessions (1): Q56A73

UniProt curated annotations — full annotation on UniProt →

Function. Binds to acetylated and methylated histones, including H3K4me3 and H4K20me3, probably acting as a histone reader that recognizes chromatin marks and mediates downstream cellular effects. Promotes canonical WNT signaling, and is involved in the down-regulation of cell proliferation.

Subunit / interactions. Interacts with C11orf84/SPINDOC. Associates with chromatin.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Lui-Jee-Baron syndrome (LJBS) [MIM:301114] An X-linked disorder characterized by prenatal onset, generalized overgrowth, extreme tall stature, enlarged liver and spleen, macrocephaly, dysmorphic features, and normal development. Hemizygous males are more severely affected than heterozygous females. The disease may be caused by variants affecting the gene represented in this entry. A variant causing frameshift and truncation of the SPIN4 protein has been found in one family with Lui-Jee-Baron syndrome. In mice, SPIN4 truncating mutations result in features recapitulating the human disease, including generalized overgrowth and increased longitudinal bone growth. Growth plate analysis of mutant mice reveales increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone.

Similarity. Belongs to the SPIN/STSY family.

RefSeq proteins (1): NP_001012986* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003671	SPIN/Ssty	Family
IPR042567	SPIN/Ssty_sf	Homologous_superfamily

Pfam: PF02513

UniProt features (29 total): strand 16, region of interest 5, turn 2, helix 2, site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4UY4	X-RAY DIFFRACTION	1.86
9T31	X-RAY DIFFRACTION	2.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q56A73-F1	82.17	0.64

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 (2): 159 (histone h3k4me3 and h3r8me2a binding); 170 (histone h3k4me3 and h3r8me2a binding)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 152 (showing top): GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CANONICAL_WNT_SIGNALING_PATHWAY, JAATINEN_HEMATOPOIETIC_STEM_CELL_UP, GOBP_POSITIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY, GRADE_COLON_AND_RECTAL_CANCER_DN, VERNELL_RETINOBLASTOMA_PATHWAY_UP, KONDO_PROSTATE_CANCER_HCP_WITH_H3K27ME3, GEORGES_TARGETS_OF_MIR192_AND_MIR215, VECCHI_GASTRIC_CANCER_EARLY_UP, WHITFIELD_CELL_CYCLE_G1_S, CHICAS_RB1_TARGETS_SENESCENT, CHICAS_RB1_TARGETS_GROWING, WANG_RESPONSE_TO_GSK3_INHIBITOR_SB216763_DN, chrXq11

GO Biological Process (5): regulation of DNA-templated transcription (GO:0006355), gamete generation (GO:0007276), negative regulation of cell population proliferation (GO:0008285), positive regulation of canonical Wnt signaling pathway (GO:0090263), chromatin organization (GO:0006325)

GO Molecular Function (2): histone H3K4me3 reader activity (GO:0140002), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
sexual reproduction	1
multicellular organismal reproductive process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
cellular component organization	1
histone H3 reader activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

288 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPIN4	ARHGEF9	O43307	512
SPIN4	GMCL1	Q96IK5	506
SPIN4	HP1BP3	Q5SSJ5	466
SPIN4	ATOSB	Q7L5A3	438
SPIN4	TAF13	Q15543	435
SPIN4	SPINDOC	Q9BUA3	400
SPIN4	C2CD5	Q86YS7	385
SPIN4	MAGEA10	P43363	383
SPIN4	CAPN6	Q9Y6Q1	382
SPIN4	ALG13	Q9NP73	379
SPIN4	C10orf71	Q711Q0	377
SPIN4	HEPH	Q9BQS7	372
SPIN4	EDA2R	Q9HAV5	372
SPIN4	KCTD3	Q9Y597	364
SPIN4	ADAM20	O43506	360

IntAct

12 interactions, top by confidence:

A	B	Type	Score
SPIN1	PAX3	psi-mi:“MI:0914”(association)	0.530
SPIN4	PRMT6	psi-mi:“MI:0914”(association)	0.530
M		psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
SPIN4	FBXO11	psi-mi:“MI:0914”(association)	0.350
PRTN3	GOLIM4	psi-mi:“MI:0914”(association)	0.350
SPIN4	MBL2	psi-mi:“MI:0914”(association)	0.350
SPIN4	DIS3L2	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): SPIN4 (Affinity Capture-RNA), SPIN4 (Affinity Capture-RNA), SPIN4 (Affinity Capture-MS), SPIN4 (Affinity Capture-MS), SPIN4 (Affinity Capture-MS), SPIN4 (Affinity Capture-MS), DCAF16 (Affinity Capture-MS), PRMT6 (Affinity Capture-MS), PKLR (Affinity Capture-MS), TPK1 (Affinity Capture-MS), MBL2 (Affinity Capture-MS), SPIN1 (Affinity Capture-MS), FBXO11 (Affinity Capture-MS), DCAF16 (Affinity Capture-Western), SPIN4 (Affinity Capture-Western)

ESM2 similar proteins: B3H754, C6KIE6, F4I8W1, F4ISV9, F4J4N3, F4K3G5, F4K487, K7TQE3, O22267, O23610, O80568, P13675, P59178, Q0WS06, Q32N90, Q500V5, Q56A73, Q683D5, Q6AUQ7, Q6DBH0, Q6NKN8, Q84WJ0, Q8K1L2, Q8RXM6, Q94HV8, Q969R5, Q9C5P0, Q9C5Q9, Q9C7I9, Q9C8N7, Q9C8N9, Q9FFA0, Q9FGS8, Q9FJX8, Q9FJX9, Q9FMV0, Q9FT92, Q9FV02, Q9FX25, Q9LG02

Diamond homologs: P13675, Q2KI39, Q4V8J7, Q56A73, Q5JUX0, Q5R997, Q5RA80, Q5RAW7, Q61142, Q6NVE3, Q8K1L2, Q90WG1, Q90WG2, Q99865, Q9BPZ2, Q9Y657

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	11
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2671851	NM_001012968.3(SPIN4):c.312_313del (p.Arg104fs)	Pathogenic

SpliceAI

88 predictions. Top by Δscore:

Variant	Effect	Δscore
X:63351164:G:C	donor_gain	0.9900
X:63351163:A:AC	donor_gain	0.9800
X:63351163:AG:A	donor_gain	0.9600
X:63350144:TCGCC:T	donor_gain	0.9500
X:63350124:A:AC	donor_gain	0.9000
X:63350180:TGG:T	donor_gain	0.8600
X:63350125:A:C	donor_gain	0.8300
X:63350805:G:T	acceptor_gain	0.8300
X:63348491:C:G	acceptor_gain	0.8100
X:63350143:TTCGC:T	donor_gain	0.7500
X:63350150:C:CT	donor_gain	0.7400
X:63350204:C:CT	donor_gain	0.7200
X:63350205:C:CT	donor_gain	0.7000
X:63350203:TC:T	donor_gain	0.6900
X:63350147:C:CT	donor_gain	0.6800
X:63351164:G:A	donor_gain	0.6400
X:63350178:CTTGG:C	donor_gain	0.6200
X:63350729:T:TA	acceptor_gain	0.5800
X:63351157:C:CT	donor_gain	0.5800
X:63348492:T:TG	acceptor_gain	0.5200
X:63350151:C:CT	donor_gain	0.5100
X:63351158:C:CT	donor_gain	0.5000
X:63350807:T:TC	acceptor_gain	0.4700
X:63350788:ACCCC:A	acceptor_gain	0.4400
X:63350789:CCCCC:C	acceptor_gain	0.4400
X:63351159:A:AC	donor_gain	0.4400
X:63351160:C:CC	donor_gain	0.4400
X:63350804:CGGT:C	acceptor_gain	0.4300
X:63351160:CTTAG:C	donor_gain	0.4300
X:63350994:CTA:C	donor_gain	0.4100

AlphaMissense

1633 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:63350439:A:C	F127L	0.999
X:63350439:A:T	F127L	0.999
X:63350441:A:G	F127L	0.999
X:63350118:A:C	F234L	0.998
X:63350118:A:T	F234L	0.998
X:63350120:A:G	F234L	0.998
X:63350293:A:G	L176S	0.998
X:63350364:A:C	F152L	0.998
X:63350364:A:T	F152L	0.998
X:63350366:A:G	F152L	0.998
X:63350673:C:A	W49C	0.997
X:63350673:C:G	W49C	0.997
X:63350440:A:C	F127C	0.996
X:63350588:A:G	Y78H	0.996
X:63350589:T:A	K77N	0.996
X:63350589:T:G	K77N	0.996
X:63350639:C:G	G61R	0.996
X:63350119:A:G	F234S	0.995
X:63350311:T:A	D170V	0.995
X:63350335:A:T	L162H	0.995
X:63350354:A:G	Y156H	0.995
X:63350398:A:T	V141D	0.995
X:63350405:C:G	G139R	0.995
X:63350440:A:G	F127S	0.995
X:63350591:T:C	K77E	0.995
X:63350629:A:T	L64H	0.995
X:63350686:A:C	I45S	0.995
X:63350686:A:G	I45T	0.995
X:63350686:A:T	I45N	0.995
X:63350121:C:A	K233N	0.994

dbSNP variants (sampled 300 via entrez): RS1053713 (X:63347590 T>C), RS111287985 (X:63347451 T>C), RS111923761 (X:63348588 G>T), RS113579085 (X:63352061 A>G), RS1156493888 (X:63352627 G>A,T), RS1156688942 (X:63351563 C>T), RS1158595894 (X:63348004 C>G,T), RS1158691165 (X:63347395 T>C), RS1159270746 (X:63353257 G>T), RS1159434178 (X:63346735 C>T), RS1159506306 (X:63352037 T>A,C), RS1159634932 (X:63349401 TAAA>T,TA,TAA), RS1159704013 (X:63351198 G>A), RS1160115370 (X:63351580 G>C,T), RS1160307389 (X:63350220 G>A)

Disease associations

OMIM: gene MIM:301113 | disease phenotypes: MIM:301114

GenCC curated gene-disease

Disease	Classification	Inheritance
Lui-Jee-Baron syndrome	Moderate	X-linked

Mondo (1): Lui-Jee-Baron syndrome (MONDO:0957919)

Orphanet (0):

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000256	Macrocephaly
HP:0000411	Protruding ear
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0001249	Intellectual disability
HP:0001417	X-linked inheritance
HP:0001520	Large for gestational age
HP:0001548	Overgrowth
HP:0001744	Splenomegaly
HP:0001763	Pes planus
HP:0002002	Deep philtrum
HP:0002240	Hepatomegaly
HP:0002343	Normal pressure hydrocephalus
HP:0003577	Congenital onset
HP:0006610	Wide intermamillary distance

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523321 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.74	Kd	18.1	nM	CHEMBL4451634
6.77	Kd	170	nM	CHEMBL4552020
6.15	Kd	710	nM	CHEMBL5594627

PubChem BioAssay actives

3 with measured affinity, of 5 total; 3 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
2-[4-[2-[[2-[3-[2-amino-5-(cyclopropylmethoxy)-3,3-dimethylindol-6-yl]oxypropyl]-1,3-dihydroisoindol-5-yl]oxy]ethyl]triazol-1-yl]-1-[4-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethanone	1526487: Binding affinity to recombinant human His-tagged SPIN4 (36 to 249 residues) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by isothermal titration calorimetry	kd	0.0181	uM
[3-(aminomethyl)-5-[3-(1,3-dihydroisoindol-2-yl)propoxy]-4-methoxyphenyl]methanamine	1578937: Inhibition of recombinant human N-terminal His6-tagged SPIN4 (36 to 249 residues) expressed in Escherichia coli BL21 (DE3) cells assessed as dissociation constant by isothermal titration calorimetry	kd	0.1700	uM
N-[7-[3-(1,3-dihydroisoindol-2-yl)propoxy]-6-methoxy-4-pyrrolidin-1-ylquinazolin-2-yl]-N’,N’-dimethylethane-1,2-diamine	2103453: Binding affinity to human N-terminal His6 tagged SPIN4 (T36 to P249 residues) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by isothermal titration calorimetry	kd	0.7100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
Valproic Acid	affects expression, decreases expression, increases expression	4
bisphenol A	affects expression, decreases expression	2
trichostatin A	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Endosulfan	decreases expression	2
Cyclosporine	decreases expression	2
triphenyl phosphate	affects expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
resorcinol	increases expression	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4323087	Binding	Binding affinity to recombinant human His-tagged SPIN4 (36 to 249 residues) expressed in Escherichia coli BL21 (DE3) assessed as melting temperature at 20 uM by Sypro orange dye based differential scanning fluorimetry	A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function. — J Med Chem

Clinical trials (associated diseases)

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