FNDC4

Summary

FNDC4 (fibronectin type III domain containing 4, HGNC:20239) is a protein-coding gene on chromosome 2p23.3, encoding Fibronectin type III domain-containing protein 4 (Q9H6D8). Has anti-inflammatory properties.

Involved in response to transforming growth factor beta. Predicted to be located in endoplasmic reticulum; extracellular space; and plasma membrane.

Source: NCBI Gene 64838 — RefSeq curated summary.

At a glance

• GWAS associations: 38
• Clinical variants (ClinVar): 21 total
• MANE Select transcript: NM_022823

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20239
Approved symbol	FNDC4
Name	fibronectin type III domain containing 4
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22362, FRCP1
Ensembl gene	ENSG00000115226
Ensembl biotype	protein_coding
OMIM	611905
Entrez	64838

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 retained_intron

ENST00000264703, ENST00000476197, ENST00000491414, ENST00000934124, ENST00000934125, ENST00000951222

RefSeq mRNA: 1 — MANE Select: NM_022823 NM_022823

CCDS: CCDS1756

Canonical transcript exons

ENST00000264703 — 7 exons

Exon	Start	End
ENSE00000809192	27492666	27492790
ENSE00000963044	27491883	27492478
ENSE00001348754	27494878	27495200
ENSE00003478690	27494547	27494703
ENSE00003515631	27493389	27493478
ENSE00003615252	27493930	27494134
ENSE00003686111	27494351	27494466

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 98.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6875 / max 193.9208, expressed in 1282 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27515	7.9840	1276
202128	0.3764	211
27512	0.1506	51
27516	0.0928	27
27514	0.0629	27
27513	0.0209	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland cortex	UBERON:0035825	98.00	gold quality
left adrenal gland	UBERON:0001234	97.87	gold quality
right adrenal gland	UBERON:0001233	97.66	gold quality
adrenal cortex	UBERON:0001235	97.05	gold quality
right adrenal gland cortex	UBERON:0035827	97.00	gold quality
right lobe of liver	UBERON:0001114	96.10	gold quality
right frontal lobe	UBERON:0002810	95.56	gold quality
adrenal gland	UBERON:0002369	95.40	gold quality
anterior cingulate cortex	UBERON:0009835	94.92	gold quality
cingulate cortex	UBERON:0003027	94.90	gold quality
prefrontal cortex	UBERON:0000451	94.84	gold quality
lower esophagus mucosa	UBERON:0035834	94.44	gold quality
cortical plate	UBERON:0005343	93.44	gold quality
neocortex	UBERON:0001950	93.41	gold quality
frontal cortex	UBERON:0001870	93.32	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.31	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.10	gold quality
nucleus accumbens	UBERON:0001882	93.09	gold quality
caudate nucleus	UBERON:0001873	92.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.77	gold quality
cerebellar hemisphere	UBERON:0002245	92.58	gold quality
left ovary	UBERON:0002119	92.54	gold quality
cerebellar cortex	UBERON:0002129	92.53	gold quality
amygdala	UBERON:0001876	92.52	gold quality
cerebral cortex	UBERON:0000956	92.00	gold quality
putamen	UBERON:0001874	91.94	gold quality
telencephalon	UBERON:0001893	91.58	gold quality
cerebellum	UBERON:0002037	91.33	gold quality
liver	UBERON:0002107	91.23	gold quality
right ovary	UBERON:0002118	91.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting FNDC4, 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-6077	99.99	68.04	2299
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-6881-5P	98.16	67.38	665
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-144-5P	97.66	69.90	531
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-4653-5P	97.22	67.72	1429
HSA-MIR-6841-5P	97.19	67.29	409
HSA-MIR-3649	96.85	64.10	340

Literature-anchored findings (GeneRIF, showing 8)

• Reports the cloning, expression and subcellular localization of the related mouse protein. (PMID:12384288)
• FNDC4 as a factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases. (PMID:27066907)
• The novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. (PMID:32407726)
• Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue. (PMID:34016966)
• FNDC4 and FNDC5 reduce SARS-CoV-2 entry points and spike glycoprotein S1-induced pyroptosis, apoptosis, and necroptosis in human adipocytes. (PMID:34465884)
• Irisin and the fibronectin type III domain-containing family: structure, signaling and role in female reproduction. (PMID:35521900)
• FNDC4 reduces inflammation, proliferation, invasion and migration of rheumatoid synovial cells by inhibiting CCL2/ERK signaling. (PMID:38181585)
• FNDC4 reduces hepatocyte inflammatory cell death via AMPKalpha in metabolic dysfunction-associated steatotic liver disease. (PMID:39173437)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fndc4	ENSMUSG00000038552
rattus_norvegicus	Fndc4	ENSRNOG00000051056

Paralogs (1): FNDC5 (ENSG00000160097)

Protein

Protein identifiers

Fibronectin type III domain-containing protein 4 — Q9H6D8 (reviewed: Q9H6D8)

Alternative names: Fibronectin type III repeat-containing protein 1

All UniProt accessions (1): Q9H6D8

UniProt curated annotations — full annotation on UniProt →

Function. Has anti-inflammatory properties. In the colon, acts on macrophages to down-regulate inflammation. May suppress osteoclastogenesis and mature osteoclast resorptive function. In white adipose tissue, decreases local inflammation, via interaction with GPR116. Also required for proper systemic glucose tolerance, specifically sensitizing white adipocytes to insulin and promoting glucose uptake. The insulin sensitizing function in adipose tissue is mediated by interaction with ADGRF5/GPR116 and activation of cAMP signaling.

Subcellular location. Membrane Secreted.

Tissue specificity. Highly expressed in the liver and the brain, including in the cortex, hypothalamus and hippocampus. Also expressed in adipose tissue.

Induction. Up-regulated by inflammation in the intestine. Up-regulated by TGFB1 in a colorectal adenocarcinoma cell line.

RefSeq proteins (1): NP_073734* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR052120	FNDC_type_III_4/5	Family

Pfam: PF00041

UniProt features (13 total): glycosylation site 3, chain 2, topological domain 2, region of interest 2, signal peptide 1, transmembrane region 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6D8-F1	70.27	0.35

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 (3): 52, 97, 147

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 78 (showing top): GOBP_INFLAMMATORY_RESPONSE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, LASTOWSKA_COAMPLIFIED_WITH_MYCN, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_GROWTH_FACTOR, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE, CUI_TCF21_TARGETS_2_UP

GO Biological Process (2): negative regulation of inflammatory response (GO:0050728), response to transforming growth factor beta (GO:0071559)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
response to growth factor	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FNDC4	FN1	P02751	643
FNDC4	ADGRF5	Q8IZF2	633
FNDC4	ZNF512	Q96ME7	594
FNDC4	EIF2B4	Q9UI10	584
FNDC4	SPATA31H1	Q68DN1	570
FNDC4	KRTCAP3	Q53RY4	565
FNDC4	ATRAID	Q6UW56	557
FNDC4	CCDC121	Q6ZUS5	542
FNDC4	SNX17	Q15036	541
FNDC4	CCDC61	Q9Y6R9	536
FNDC4	NRBP1	Q9UHY1	512
FNDC4	PINLYP	A6NC86	505
FNDC4	FNDC3A	Q9Y2H6	505
FNDC4	GTF3C2	Q8WUA4	469
FNDC4	HIC2	Q96JB3	462

IntAct

4 interactions, top by confidence:

A	B	Type	Score
FNDC4	POLR2G	psi-mi:“MI:0915”(physical association)	0.370
FNDC4	MT-ND2	psi-mi:“MI:0914”(association)	0.350
FNDC4	NDUFB3	psi-mi:“MI:0914”(association)	0.350

BioGRID (39): SAFB2 (Affinity Capture-MS), GHITM (Affinity Capture-MS), AGPAT3 (Affinity Capture-MS), LIMA1 (Affinity Capture-MS), GALNT11 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), CAV1 (Affinity Capture-MS), NDUFB3 (Affinity Capture-MS), INTS7 (Affinity Capture-MS), PPP1R10 (Affinity Capture-MS), MPRIP (Affinity Capture-MS), ND5 (Affinity Capture-MS), ALG10 (Affinity Capture-MS), HLA-DRB1 (Affinity Capture-MS)

ESM2 similar proteins: A6NLX4, A6QNY1, A6QPL2, A9CBA0, B2RTN2, D3ZF92, O43278, O75509, O88472, P30203, P98154, P98162, Q1JQE1, Q1RMT9, Q29RT9, Q3U515, Q56A20, Q5BIR3, Q5HZW5, Q5RCS3, Q5XIX0, Q61003, Q64322, Q6AXU5, Q6UWV7, Q7TMJ8, Q7TQH7, Q7Z4F1, Q86T13, Q86XT9, Q8BH27, Q8BSU2, Q8CB67, Q8TEF2, Q8VCP9, Q91ZV2, Q91ZV3, Q921R4, Q96FE7, Q96PD2

Diamond homologs: A6QPL2, O18016, O18023, Q1L867, Q3TR08, Q8K3V5, Q8K4Z2, Q8NAU1, Q8WZ42, Q98949, Q9H6D8, B0V2N1, F1NWE3, G5EF96, Q13332, Q64605, Q8AV57, P16621

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

895 predictions. Top by Δscore:

Variant	Effect	Δscore
2:27492476:TTTC:T	acceptor_loss	1.0000
2:27492477:TTCTG:T	acceptor_loss	1.0000
2:27492478:TC:T	acceptor_loss	1.0000
2:27492479:C:CC	acceptor_gain	1.0000
2:27492479:CTGT:C	acceptor_loss	1.0000
2:27492687:T:TA	donor_gain	1.0000
2:27492688:C:A	donor_gain	1.0000
2:27492788:CAG:C	acceptor_gain	1.0000
2:27492791:C:CC	acceptor_gain	1.0000
2:27493383:A:AC	donor_gain	1.0000
2:27493384:C:CC	donor_gain	1.0000
2:27493385:TCAC:T	donor_loss	1.0000
2:27493386:CAC:C	donor_loss	1.0000
2:27493387:A:AC	donor_gain	1.0000
2:27493387:ACCAG:A	donor_gain	1.0000
2:27493388:C:CC	donor_gain	1.0000
2:27493388:CCAG:C	donor_gain	1.0000
2:27493388:CCAGC:C	donor_gain	1.0000
2:27493407:C:CT	donor_gain	1.0000
2:27493427:T:TA	donor_gain	1.0000
2:27493428:C:A	donor_gain	1.0000
2:27493475:TCAC:T	acceptor_gain	1.0000
2:27493476:CACC:C	acceptor_gain	1.0000
2:27493479:C:CA	acceptor_loss	1.0000
2:27493479:C:CC	acceptor_gain	1.0000
2:27494349:A:AC	donor_gain	1.0000
2:27494350:C:CC	donor_gain	1.0000
2:27494350:CTTG:C	donor_gain	1.0000
2:27494462:CCGGT:C	acceptor_gain	1.0000
2:27494463:CGGT:C	acceptor_gain	1.0000

AlphaMissense

1498 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:27493395:A:G	W180R	1.000
2:27493395:A:T	W180R	1.000
2:27494399:C:A	W67C	1.000
2:27494399:C:G	W67C	1.000
2:27494401:A:G	W67R	0.999
2:27494401:A:T	W67R	0.999
2:27492774:G:C	F187L	0.998
2:27492774:G:T	F187L	0.998
2:27492776:A:G	F187L	0.998
2:27494400:C:G	W67S	0.998
2:27494412:G:T	A63D	0.998
2:27493980:A:G	F135S	0.997
2:27494368:A:C	Y78D	0.997
2:27494436:A:T	V55D	0.997
2:27493980:A:C	F135C	0.996
2:27494361:A:T	I80N	0.996
2:27494370:C:T	G77D	0.996
2:27494400:C:A	W67L	0.996
2:27493979:G:C	F135L	0.995
2:27493979:G:T	F135L	0.995
2:27493981:A:G	F135L	0.995
2:27494066:C:A	W106C	0.995
2:27494066:C:G	W106C	0.995
2:27494416:A:G	S62P	0.995
2:27492784:A:T	I184N	0.994
2:27494406:A:T	V65E	0.994
2:27492750:C:A	K195N	0.993
2:27492750:C:G	K195N	0.993
2:27492775:A:G	F187S	0.993
2:27494070:A:T	L105H	0.993

dbSNP variants (sampled 300 via entrez): RS1000571428 (2:27492517 G>C), RS1001692053 (2:27495844 G>A,T), RS1001797559 (2:27497146 G>A), RS1002560298 (2:27496293 G>T), RS1002694619 (2:27495977 T>C), RS1003144153 (2:27492847 C>A), RS1003562709 (2:27495216 C>T), RS1003708065 (2:27494889 C>A,T), RS1004765645 (2:27496328 T>C), RS1005637442 (2:27494914 G>A,C), RS1005733035 (2:27494905 C>A), RS1005764269 (2:27495231 C>G), RS1006001097 (2:27495078 C>T), RS1007502218 (2:27495330 AC>A), RS1007824753 (2:27491673 T>A,C)

Disease associations

OMIM: gene MIM:611905 | disease phenotypes: MIM:615630, MIM:616394

GenCC curated gene-disease

Mondo (2): short-rib thoracic dysplasia 10 with or without polydactyly (MONDO:0014284), retinitis pigmentosa 71 (MONDO:0014618)

Orphanet (2): Jeune syndrome (Orphanet:474), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

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

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000649_21	Chronic kidney disease	3.000000e-14
GCST000769_3	Calcium levels	7.000000e-06
GCST001381_11	Menopause (age at onset)	2.000000e-12
GCST001698_12	Serum total protein levels	4.000000e-06
GCST001698_9	Serum total protein levels	6.000000e-08
GCST001699_7	Serum albumin levels	3.000000e-14
GCST001699_9	Serum albumin levels	2.000000e-08
GCST001905_4	Hypertriglyceridemia	2.000000e-13
GCST002650_1	Coffee consumption (cups per day)	7.000000e-08
GCST004131_72	Inflammatory bowel disease	1.000000e-07
GCST004132_64	Crohn’s disease	6.000000e-11
GCST009391_1135	Metabolite levels	1.000000e-09
GCST009391_1193	Metabolite levels	8.000000e-12
GCST009391_1334	Metabolite levels	7.000000e-08
GCST009391_134	Metabolite levels	5.000000e-06
GCST009391_1399	Metabolite levels	3.000000e-06
GCST009391_1436	Metabolite levels	2.000000e-07
GCST009391_1449	Metabolite levels	3.000000e-08
GCST009391_1458	Metabolite levels	5.000000e-08
GCST009391_1504	Metabolite levels	3.000000e-07
GCST009391_1521	Metabolite levels	3.000000e-06
GCST009391_1600	Metabolite levels	3.000000e-08
GCST009391_1613	Metabolite levels	7.000000e-08
GCST009391_1731	Metabolite levels	6.000000e-06
GCST009391_1763	Metabolite levels	6.000000e-06
GCST009391_1815	Metabolite levels	1.000000e-06
GCST009391_1821	Metabolite levels	2.000000e-08
GCST009391_1832	Metabolite levels	2.000000e-07
GCST009391_1840	Metabolite levels	1.000000e-07
GCST009391_1867	Metabolite levels	3.000000e-09

EFO canonical traits (33, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement
EFO:0004704	age at menopause
EFO:0004536	total blood protein measurement
EFO:0004530	triglyceride measurement
EFO:0004330	coffee consumption
EFO:0006782	cups of coffee per day measurement
EFO:0010458	alpha-hydroxybutyric acid measurement
EFO:0009765	alanine measurement
EFO:0010362	lysophosphatidylcholine 20:3 measurement
EFO:0010355	diacylglycerol 36:2 measurement
EFO:0010369	lysophosphatidylethanolamine 18:2 measurement
EFO:0010409	triacylglycerol 50:2 measurement
EFO:0010410	triacylglycerol 50:3 measurement
EFO:0010406	triacylglycerol 48:3 measurement
EFO:0010417	triacylglycerol 52:5 measurement
EFO:0010418	triacylglycerol 52:6 measurement
EFO:0010377	phosphatidylcholine 34:3 measurement
EFO:0010378	phosphatidylcholine 34:4 measurement
EFO:0010375	phosphatidylcholine 34:1 measurement
EFO:0010370	lysophosphatidylethanolamine 20:4 measurement
EFO:0010404	triacylglycerol 48:1 measurement
EFO:0010405	triacylglycerol 48:2 measurement
EFO:0010412	triacylglycerol 50:5 measurement
EFO:0010413	triacylglycerol 52:1 measurement
EFO:0010411	triacylglycerol 50:4 measurement
EFO:0010414	triacylglycerol 52:2 measurement
EFO:0010373	phosphatidylcholine 32:1 measurement
EFO:0010374	phosphatidylcholine 32:2 measurement
EFO:0007745	lactate measurement
EFO:0010356	lysophosphatidylcholine 14:0 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, affects methylation	3
Fluoxetine	increases expression	3
Ketoconazole	increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Amiodarone	increases expression	2
Amitriptyline	increases expression	2
Chlorpromazine	increases expression	2
Clozapine	increases expression	2
Flecainide	decreases expression, increases expression	2
Imipramine	increases expression	2
Perhexiline	increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tamoxifen	increases expression	2
Thioridazine	increases expression	2
Valproic Acid	decreases methylation, affects expression	2
Zimeldine	increases expression	2
Cyclosporine	increases expression	2
Sertraline	increases expression	2
bisphenol A	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
diallyl trisulfide	increases expression	1
chlorcyclizine	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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