MMRN2

Summary

MMRN2 (multimerin 2, HGNC:19888) is a protein-coding gene on chromosome 10q23.2, encoding Multimerin-2 (Q9H8L6). Extracellular matrix protein that plays significant roles in the vascular system and is required for the maintenance and stability of blood vessel.

This gene encodes a protein belonging to the member of elastin microfibril interface-located (EMILIN) protein family. This family member is an extracellular matrix glycoprotein that can interfere with tumor angiogenesis and growth. It serves as a transforming growth factor beta antagonist and can interfere with the VEGF-A/VEGFR2 pathway. A related pseudogene has been identified on chromosome 6.

Source: NCBI Gene 79812 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 319 total
• MANE Select transcript: NM_024756

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19888
Approved symbol	MMRN2
Name	multimerin 2
Location	10q23.2
Locus type	gene with protein product
Status	Approved
Aliases	EndoGlyx-1, FLJ13465
Ensembl gene	ENSG00000173269
Ensembl biotype	protein_coding
OMIM	608925
Entrez	79812

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000372027, ENST00000474994, ENST00000488950, ENST00000608090, ENST00000608753, ENST00000609457, ENST00000610081, ENST00000896187, ENST00000896188, ENST00000896189, ENST00000896190, ENST00000896191

RefSeq mRNA: 1 — MANE Select: NM_024756 NM_024756

CCDS: CCDS7379

Canonical transcript exons

ENST00000372027 — 7 exons

Exon	Start	End
ENSE00001210182	86942317	86944128
ENSE00001210186	86944262	86944435
ENSE00001858285	86935540	86937125
ENSE00003350406	86945188	86945268
ENSE00003386540	86945370	86945476
ENSE00003688241	86945561	86945689
ENSE00003704170	86957378	86957615

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 94.63.

FANTOM5 (CAGE): breadth broad, TPM avg 7.6368 / max 257.9862, expressed in 425 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110419	5.2466	351
110418	1.9405	285
187282	0.8789	378
110420	0.3233	150
110422	0.0966	51
110421	0.0298	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
subcutaneous adipose tissue	UBERON:0002190	94.63	gold quality
omental fat pad	UBERON:0010414	94.08	gold quality
peritoneum	UBERON:0002358	94.03	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.03	gold quality
adipose tissue	UBERON:0001013	93.84	gold quality
apex of heart	UBERON:0002098	93.15	gold quality
connective tissue	UBERON:0002384	92.99	gold quality
pericardium	UBERON:0002407	92.69	gold quality
endothelial cell	CL:0000115	92.10	gold quality
urethra	UBERON:0000057	91.37	gold quality
sural nerve	UBERON:0015488	91.01	gold quality
superficial temporal artery	UBERON:0001614	90.39	gold quality
heart left ventricle	UBERON:0002084	90.11	gold quality
cardiac ventricle	UBERON:0002082	90.05	gold quality
mucosa of stomach	UBERON:0001199	89.95	gold quality
visceral pleura	UBERON:0002401	89.92	gold quality
parietal pleura	UBERON:0002400	89.73	gold quality
body of uterus	UBERON:0009853	89.65	gold quality
right coronary artery	UBERON:0001625	89.61	gold quality
pleura	UBERON:0000977	89.54	gold quality
vena cava	UBERON:0004087	89.54	gold quality
seminal vesicle	UBERON:0000998	89.21	gold quality
left uterine tube	UBERON:0001303	89.18	gold quality
heart	UBERON:0000948	89.07	gold quality
tibial artery	UBERON:0007610	89.03	gold quality
popliteal artery	UBERON:0002250	88.99	gold quality
upper lobe of left lung	UBERON:0008952	88.92	gold quality
right lobe of thyroid gland	UBERON:0001119	88.83	gold quality
tibial nerve	UBERON:0001323	88.79	gold quality
left coronary artery	UBERON:0001626	88.74	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	369.38
E-MTAB-10287	yes	64.43
E-GEOD-135922	yes	47.12
E-HCAD-11	yes	43.90
E-MTAB-8410	yes	29.48
E-MTAB-9067	yes	6.85
E-MTAB-5061	yes	5.79
E-CURD-112	yes	4.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting MMRN2, 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-340-5P	100.00	72.50	4437
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4271	99.88	68.32	2244
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053

Literature-anchored findings (GeneRIF, showing 6)

• CLEC14A is a matrix component which binds to MMRN2 in the process of endothelial cells transformation in tumor angiogenesis. (PMID:23979707)
• Results suggest that CLEC14A-MMRN2 binding has a role in inducing sprouting angiogenesis during tumor growth, which has the potential to be manipulated in future antiangiogenic therapy design. (PMID:25745997)
• These findings identify novel protein interactions involving CLEC14A, CD93 and CD248 with MMRN2 as targetable components of vessel formation (PMID:28671670)
• Data identify MMRN2 as a specific ligand for CD93. CD93 and MMRN2 are co-expressed in the blood vessels of various tumors. Moreover, disruption of the CD93-MMRN2 interaction reduced endothelial cell adhesion and migration. Site-directed mutagenesis identified different residue hotspots either directly or indirectly involved in the binding and propose a molecular model in which the coiled-coil domain of MMRN2 is engaged. (PMID:28912033)
• Loss of Multimerin-2 and EMILIN-2 Expression in Gastric Cancer Associate with Altered Angiogenesis (PMID:30544909)
• Multimerin-2 maintains vascular stability and permeability. (PMID:31422156)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmrn2b	ENSDARG00000073711
danio_rerio	mmrn2a	ENSDARG00000076135
mus_musculus	Mmrn2	ENSMUSG00000041445
rattus_norvegicus	Mmrn2	ENSRNOG00000051977

Paralogs (4): EMILIN2 (ENSG00000132205), EMILIN1 (ENSG00000138080), MMRN1 (ENSG00000138722), EMILIN3 (ENSG00000183798)

Protein

Protein identifiers

Multimerin-2 — Q9H8L6 (reviewed: Q9H8L6)

Alternative names: EMILIN-3, Elastin microfibril interface located protein 3, EndoGlyx-1 p125/p140 subunit

All UniProt accessions (5): Q9H8L6, R4GMY6, V9GY37, V9GY43, V9GYS9

UniProt curated annotations — full annotation on UniProt →

Function. Extracellular matrix protein that plays significant roles in the vascular system and is required for the maintenance and stability of blood vessel. Affects several essential steps in angiogenesis including endothelial cell proliferation, migration, and tube formation. Positively regulates angiogenesis by acting as a ligand for CD93 receptor.

Subunit / interactions. Heteromer of p110, p125, p140 and p200 subunits; disulfide-linked. Interacts with VEGFA. Interacts with CD93; this interaction promotes angiogenesis. Interacts with CD248.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Endothelium.

Post-translational modifications. N- and O-glycosylated. O-fucosylated within the EMI domain (at Ser-63, Thr-67 and Thr-115) by POFUT3 and POFUT4. Processed by matrix metalloproteinases (MMPs) including MMP9 and, to a lesser degree, by MMP2 upon angiogenic stimulation.

RefSeq proteins (1): NP_079032* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001073	C1q_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR011489	EMI_domain	Domain
IPR050392	Collagen/C1q_domain	Family

Pfam: PF00386, PF07546

UniProt features (34 total): glycosylation site 14, sequence variant 5, coiled-coil region 4, disulfide bond 3, domain 2, region of interest 2, signal peptide 1, chain 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H8L6-F1	66.64	0.09

Functional residue map

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

Disulfide bonds (3): 58–122, 85–92, 121–130

Glycosylation sites (14): 63, 67, 115, 205, 214, 249, 261, 350, 379, 439, 472, 727, 765, 845

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5173105	O-linked glycosylation

MSigDB gene sets: 257 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, AP1_01, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_CELL_MIGRATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, AP4_Q6, HEIDENBLAD_AMPLICON_8Q24_DN, CAGCTG_AP4_Q5, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS

GO Biological Process (12): angiogenesis (GO:0001525), cell migration involved in sprouting angiogenesis (GO:0002042), cell adhesion (GO:0007155), negative regulation of cell population proliferation (GO:0008285), negative regulation of cell migration (GO:0030336), negative regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030948), negative regulation of cell migration involved in sprouting angiogenesis (GO:0090051), positive regulation of defense response to bacterium (GO:1900426), negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:1903588), positive regulation of epithelial tube formation (GO:1905278), positive regulation of morphogenesis of an epithelium (GO:1905332), signal transduction (GO:0007165)

GO Molecular Function (3): receptor ligand activity (GO:0048018), extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515)

GO Cellular Component (7): basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), multimerin complex (GO:1990972), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
extracellular matrix	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
negative regulation of signal transduction	1
regulation of vascular endothelial growth factor receptor signaling pathway	1
vascular endothelial growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
cell migration involved in sprouting angiogenesis	1
negative regulation of blood vessel endothelial cell migration	1
regulation of cell migration involved in sprouting angiogenesis	1
positive regulation of response to biotic stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
defense response to bacterium	1
regulation of defense response to bacterium	1
negative regulation of endothelial cell proliferation	1
blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1
regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1
positive regulation of multicellular organismal process	1
epithelial tube formation	1
regulation of epithelial tube formation	1
positive regulation of morphogenesis of an epithelium	1
morphogenesis of an epithelium	1
positive regulation of developmental process	1
regulation of morphogenesis of an epithelium	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signaling receptor binding	1
signal transduction	1

Protein interactions and networks

STRING

1299 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMRN2	CLEC14A	Q86T13	864
MMRN2	FAM25A	B3EWG3	468
MMRN2	CD93	Q9NPY3	460
MMRN2	EMID1	Q96A84	441
MMRN2	FKBPL	Q9UIM3	434
MMRN2	AGRN	O00468	421
MMRN2	CD248	Q9HCU0	412
MMRN2	VWA1	Q6PCB0	409
MMRN2	TSPAN4	O14817	393
MMRN2	PTK2	Q05397	391
MMRN2	NHSL2	Q5HYW2	390
MMRN2	ITGA6	P23229	383
MMRN2	CTIF	O43310	379
MMRN2	TMEM237	Q96Q45	370
MMRN2	MC2R	Q01718	369

IntAct

11 interactions, top by confidence:

A	B	Type	Score
RHBDD2	MMRN2	psi-mi:“MI:0915”(physical association)	0.560
CVC2	MMRN2	psi-mi:“MI:0915”(physical association)	0.370
MMRN2	VDR	psi-mi:“MI:0915”(physical association)	0.370
	MMRN2	psi-mi:“MI:0915”(physical association)	0.370
	CCN1	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CDH5	MYO1C	psi-mi:“MI:2364”(proximity)	0.270
MMRN2	RHBDD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): MMRN2 (Affinity Capture-MS), MMRN2 (Affinity Capture-Western), MMRN2 (Two-hybrid), MMRN2 (Affinity Capture-Western), MMRN2 (Reconstituted Complex), MMRN2 (Co-localization), MMRN2 (Affinity Capture-RNA), MMRN2 (Biochemical Activity), MMRN2 (Affinity Capture-MS), VDR (Two-hybrid)

ESM2 similar proteins: A2AV25, A5PJQ2, O35764, O43278, O43827, O70165, O95841, O95897, P02675, P02678, P04115, P12804, P14480, P30203, P33573, Q0P4P2, Q14314, Q1RMR1, Q24K15, Q29041, Q29042, Q29RY7, Q2KJ51, Q2TNK5, Q568Y7, Q5EA66, Q5FB95, Q5I2E5, Q5XK91, Q640P2, Q6AX44, Q6TMA8, Q8BM13, Q8IUK5, Q8K0E8, Q8N539, Q8NI99, Q8R0Z6, Q8R1Q3, Q91ZV7

Diamond homologs: A6H6E2, F1QC17, P59900, Q13201, Q8K482, Q91VF6, Q96A83, Q96A84, Q99K41, Q9BXX0, Q9H8L6, Q9NT22, Q9Y6C2, Q91VF5, B2RPV6, P83425, Q4ZJM7, Q5FVH0, Q8K479, Q8R066, Q9BXJ0, Q9BXJ3, P27658, Q7Z5L3, Q8CFR0, A6NHN0, Q0II24

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	281
Likely benign	18
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2394 predictions. Top by Δscore:

Variant	Effect	Δscore
10:86937126:C:CC	acceptor_gain	1.0000
10:86942391:T:TA	donor_gain	1.0000
10:86944127:CT:C	acceptor_gain	1.0000
10:86944282:T:TA	donor_gain	1.0000
10:86945186:A:AC	donor_gain	1.0000
10:86945186:A:AT	donor_loss	1.0000
10:86945187:C:CC	donor_gain	1.0000
10:86945202:A:AC	donor_gain	1.0000
10:86945203:C:CC	donor_gain	1.0000
10:86945211:T:TA	donor_gain	1.0000
10:86945264:GGAAT:G	acceptor_gain	1.0000
10:86945265:GAAT:G	acceptor_gain	1.0000
10:86945266:AAT:A	acceptor_gain	1.0000
10:86945267:AT:A	acceptor_gain	1.0000
10:86945268:TC:T	acceptor_loss	1.0000
10:86945269:C:CA	acceptor_loss	1.0000
10:86945269:C:CC	acceptor_gain	1.0000
10:86945366:CTACC:C	donor_loss	1.0000
10:86945367:TACC:T	donor_loss	1.0000
10:86945368:A:AC	donor_gain	1.0000
10:86945369:C:A	donor_loss	1.0000
10:86945369:C:CC	donor_gain	1.0000
10:86945474:TAC:T	acceptor_gain	1.0000
10:86945475:AC:A	acceptor_gain	1.0000
10:86945476:CC:C	acceptor_gain	1.0000
10:86945477:CT:C	acceptor_loss	1.0000
10:86945559:A:AC	donor_gain	1.0000
10:86945560:C:CC	donor_gain	1.0000
10:86945560:CATGA:C	donor_gain	1.0000
10:86958786:C:G	donor_gain	1.0000

AlphaMissense

6183 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:86943424:A:G	S454P	0.987
10:86943420:A:G	L455P	0.986
10:86943372:A:G	L471P	0.985
10:86945381:C:G	C130S	0.984
10:86945382:A:T	C130S	0.984
10:86945408:C:G	C121S	0.982
10:86945409:A:T	C121S	0.982
10:86943435:A:G	L450P	0.981
10:86945413:C:A	W119C	0.980
10:86945413:C:G	W119C	0.980
10:86943429:T:A	E452V	0.978
10:86943447:A:G	L446P	0.976
10:86943529:A:G	S419P	0.976
10:86945681:C:G	C58S	0.975
10:86945682:A:T	C58S	0.975
10:86945381:C:T	C130Y	0.972
10:86936985:A:C	Y870D	0.971
10:86942996:G:C	F596L	0.971
10:86942996:G:T	F596L	0.971
10:86942998:A:G	F596L	0.971
10:86943381:A:G	L468P	0.971
10:86943428:C:A	E452D	0.970
10:86943428:C:G	E452D	0.970
10:86936765:C:T	G943D	0.969
10:86943309:C:T	C492Y	0.969
10:86943444:C:G	R447P	0.969
10:86937008:A:G	F862S	0.968
10:86943540:A:G	L415P	0.968
10:86942531:G:C	F751L	0.967
10:86942531:G:T	F751L	0.967

dbSNP variants (sampled 300 via entrez): RS1000069376 (10:86958989 A>G), RS1000113071 (10:86943322 A>G), RS1000213699 (10:86935449 C>G,T), RS1000359594 (10:86946592 G>A,T), RS1000626752 (10:86935708 T>A), RS1000710933 (10:86935681 A>G), RS1000901777 (10:86941283 A>G), RS1000952471 (10:86947578 G>A), RS1000997324 (10:86935953 G>T), RS1001004701 (10:86947800 C>T), RS1001014929 (10:86952787 C>T), RS1001156048 (10:86941003 G>A), RS1001473450 (10:86958039 A>G), RS1001607840 (10:86941710 G>A,T), RS1001802359 (10:86942590 C>G,T)

Disease associations

OMIM: gene MIM:608925 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002701_17	Verbal declarative memory	7.000000e-06
GCST002701_18	Verbal declarative memory	7.000000e-06
GCST003818_33	Resting heart rate	1.000000e-08
GCST006585_2272	Blood protein levels	4.000000e-43
GCST006661_160	Male-pattern baldness	2.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	3
aristolochic acid I	increases expression	1
fluorene-9-bisphenol	decreases expression	1
titanium dioxide	increases expression	1
decabromobiphenyl ether	increases expression	1
dimethylselenide	increases expression, increases oxidation	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
monomethylarsonous acid	decreases expression	1
abrine	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases methylation	1
Benzo(a)pyrene	affects methylation	1
Estradiol	affects cotreatment, decreases expression	1
Folic Acid	decreases expression	1
Lipopolysaccharides	increases expression, affects cotreatment, decreases expression, affects response to substance	1
Ozone	increases expression, increases oxidation	1
Silicon Dioxide	increases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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