LRFN2

Summary

LRFN2 (leucine rich repeat and fibronectin type III domain containing 2, HGNC:21226) is a protein-coding gene on chromosome 6p21.2-p21.1, encoding Leucine-rich repeat and fibronectin type-III domain-containing protein 2 (Q9ULH4). Promotes neurite outgrowth in hippocampal neurons.

Predicted to be involved in modulation of chemical synaptic transmission and regulation of postsynapse organization. Predicted to be located in plasma membrane. Predicted to be active in several cellular components, including Schaffer collateral - CA1 synapse; cell surface; and postsynaptic density membrane.

Source: NCBI Gene 57497 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 115 total
• MANE Select transcript: NM_020737

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21226
Approved symbol	LRFN2
Name	leucine rich repeat and fibronectin type III domain containing 2
Location	6p21.2-p21.1
Locus type	gene with protein product
Status	Approved
Aliases	FIGLER2
Ensembl gene	ENSG00000156564
Ensembl biotype	protein_coding
OMIM	612808
Entrez	57497

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000338305, ENST00000700335

RefSeq mRNA: 1 — MANE Select: NM_020737 NM_020737

CCDS: CCDS34443

Canonical transcript exons

ENST00000338305 — 3 exons

Exon	Start	End
ENSE00001374558	40431714	40433131
ENSE00001459695	40391591	40392912
ENSE00001459698	40586941	40587364

Expression profiles

Bgee: expression breadth broad, 66 present calls, max score 79.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9888 / max 66.9200, expressed in 129 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73510	0.7419	115
73511	0.0869	45
73508	0.0470	13
73507	0.0448	14
73509	0.0382	29
73512	0.0302	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	79.44	gold quality
prefrontal cortex	UBERON:0000451	75.82	gold quality
right frontal lobe	UBERON:0002810	73.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.75	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	71.60	gold quality
islet of Langerhans	UBERON:0000006	71.53	gold quality
frontal cortex	UBERON:0001870	71.37	gold quality
anterior cingulate cortex	UBERON:0009835	71.34	gold quality
neocortex	UBERON:0001950	70.69	gold quality
cerebral cortex	UBERON:0000956	67.28	gold quality
amygdala	UBERON:0001876	65.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.13	gold quality
cerebellar cortex	UBERON:0002129	64.81	gold quality
cerebellar hemisphere	UBERON:0002245	64.78	gold quality
hypothalamus	UBERON:0001898	64.19	gold quality
cerebellum	UBERON:0002037	63.29	gold quality
Ammon’s horn	UBERON:0001954	59.83	gold quality
temporal lobe	UBERON:0001871	59.73	gold quality
forebrain	UBERON:0001890	59.51	gold quality
brain	UBERON:0000955	59.45	gold quality
superior frontal gyrus	UBERON:0002661	57.98	gold quality
primary visual cortex	UBERON:0002436	57.12	gold quality
ganglionic eminence	UBERON:0004023	57.01	gold quality
postcentral gyrus	UBERON:0002581	55.85	silver quality
substantia nigra	UBERON:0002038	54.03	gold quality
heart right ventricle	UBERON:0002080	54.03	gold quality
parietal lobe	UBERON:0001872	53.36	silver quality
occipital lobe	UBERON:0002021	53.25	gold quality
entorhinal cortex	UBERON:0002728	52.97	silver quality
nasal cavity epithelium	UBERON:0005384	52.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting LRFN2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-6769B-5P	98.73	64.91	1092

Literature-anchored findings (GeneRIF, showing 7)

• enrichment of SALM1 on the cell surface affects dendritic arborization, and intracellular motifs regulate its dendritic versus axonal localization. (PMID:22174418)
• Microdeletion encompassing LRFN2 gene segregates with working memory deficits and learning disabilities in three family members. (PMID:26486473)
• study demonstrated that the polymorphisms rs2494938 at 6p21.1 and rs2285947 at 7p15.3 may serve as independent prognostic biomarkers for ESCC, implying the potential biological role of their related genes (LRFN2 and DNAH11) in the process of ESCC development (PMID:31053115)
• No significant association of variant rs2494938 of LRFN2 was observed with ovarian canceror breast cancer in a cohort of women in India. (PMID:31605628)
• LRFN2 gene variant rs2494938 provides susceptibility to esophageal cancer in the population of Jammu and Kashmir. (PMID:32880595)
• LRFN2 binding to NMDAR inhibits the progress of ESCC via regulating the Wnt/beta-Catenin and NF-kappaB signaling pathway. (PMID:35879265)
• Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8[+] T cell infiltration and functional transition. (PMID:37802603)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrfn2b	ENSDARG00000077489
danio_rerio	LRFN2	ENSDARG00000106248
mus_musculus	Lrfn2	ENSMUSG00000040490
rattus_norvegicus	Lrfn2	ENSRNOG00000011803

Paralogs (25): SLITRK3 (ENSG00000121871), LRFN3 (ENSG00000126243), LRFN1 (ENSG00000128011), SLIT2 (ENSG00000145147), LRRC38 (ENSG00000162494), SLITRK5 (ENSG00000165300), LRFN5 (ENSG00000165379), LRTM2 (ENSG00000166159), LINGO1 (ENSG00000169783), LRRN2 (ENSG00000170382), LRRN3 (ENSG00000173114), LRFN4 (ENSG00000173621), LINGO2 (ENSG00000174482), LRRN1 (ENSG00000175928), SLITRK1 (ENSG00000178235), GP5 (ENSG00000178732), SLITRK4 (ENSG00000179542), LRRC55 (ENSG00000183908), SLIT3 (ENSG00000184347), SLITRK6 (ENSG00000184564), SLITRK2 (ENSG00000185985), LRRC70 (ENSG00000186105), SLIT1 (ENSG00000187122), TLR9 (ENSG00000239732), TPBGL (ENSG00000261594)

Protein

Protein identifiers

Leucine-rich repeat and fibronectin type-III domain-containing protein 2 — Q9ULH4 (reviewed: Q9ULH4)

Alternative names: Synaptic adhesion-like molecule 1

All UniProt accessions (2): Q9ULH4, A0A8V8TQ63

UniProt curated annotations — full annotation on UniProt →

Function. Promotes neurite outgrowth in hippocampal neurons. Enhances the cell surface expression of 2 NMDA receptor subunits GRIN1 and GRIN2A. May play a role in redistributing DLG4 to the cell periphery.

Subunit / interactions. Forms heteromeric complexes with LRFN1, LRFN3, LRFN4 and LRFN5. Can form homomeric complexes, but not across cell junctions. Directly interacts with 2 NMDA receptor subunits GRIN1 and GRIN2A. Interacts with DLG1, DLG2, DLG3 and DLG4.

Subcellular location. Membrane. Synapse. Postsynaptic cell membrane.

Post-translational modifications. Glycosylated.

Domain organisation. The PDZ-binding motif is required for cell surface expression, neurite outgrowth promotion. This motif is also involved in DLG1-, DLG3- and DLG4-binding.

Similarity. Belongs to the LRFN family.

RefSeq proteins (1): NP_065788* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050467	LRFN	Family

Pfam: PF00041, PF07679, PF13855

UniProt features (32 total): repeat 7, domain 4, region of interest 4, compositionally biased region 4, glycosylation site 4, topological domain 2, signal peptide 1, chain 1, short sequence motif 1, disulfide bond 1, transmembrane region 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULH4-F1	70.36	0.45

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 (1): 310–359

Glycosylation sites (4): 29, 332, 341, 384

Mutagenesis-validated functional residues (1):

Position	Phenotype
787–789	loss of dlg1-, dlg3- and dlg4-binding.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8849932	Synaptic adhesion-like molecules
R-HSA-112316	Neuronal System
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 77 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOCC_CELL_SURFACE, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_JUNCTION_ORGANIZATION, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_SYNAPTIC_SIGNALING, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOCC_POSTSYNAPSE, CTGAGCC_MIR24, GOCC_SYNAPSE, GOCC_POSTSYNAPTIC_MEMBRANE, GOCC_PLASMA_MEMBRANE_REGION, GOCC_PRESYNAPSE, GOCC_SYNAPTIC_MEMBRANE

GO Biological Process (2): modulation of chemical synaptic transmission (GO:0050804), regulation of postsynapse organization (GO:0099175)

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

GO Cellular Component (9): plasma membrane (GO:0005886), cell surface (GO:0009986), Schaffer collateral - CA1 synapse (GO:0098685), presynapse (GO:0098793), postsynaptic density membrane (GO:0098839), membrane (GO:0016020), synapse (GO:0045202), postsynaptic membrane (GO:0045211), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
synapse	3
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
regulation of synapse organization	1
postsynapse organization	1
binding	1
membrane	1
cell periphery	1
postsynaptic density	1
postsynaptic membrane	1
postsynaptic specialization membrane	1
cell junction	1
synaptic membrane	1
postsynapse	1

Protein interactions and networks

STRING

1762 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRFN2	DLG4	P78352	881
LRFN2	DLG3	Q92796	876
LRFN2	DLG1	Q12959	860
LRFN2	GRIN1	P35437	720
LRFN2	FN1	P02751	605
LRFN2	UNC5CL	Q8IV45	570
LRFN2	GRIN2A	Q12879	542
LRFN2	PRTG	Q2VWP7	540
LRFN2	C6orf132	Q5T0Z8	506
LRFN2	PTPRF	P10586	485
LRFN2	PTPRS	Q13332	422
LRFN2	IGSF11	Q5DX21	406
LRFN2	DAAM2	Q86T65	405
LRFN2	TUFT1	Q9NNX1	403
LRFN2	MOCS1	Q9NZB8	399
LRFN2	GRIN3A	Q8TCU5	399

IntAct

7 interactions, top by confidence:

A	B	Type	Score
LRFN2	PTPRD	psi-mi:“MI:0407”(direct interaction)	0.440
LRFN2	PTPRF	psi-mi:“MI:0407”(direct interaction)	0.440
PTPRS	LRFN2	psi-mi:“MI:0407”(direct interaction)	0.440
VEZT	S100A11	psi-mi:“MI:0914”(association)	0.350
PNPT1	PDE12	psi-mi:“MI:0914”(association)	0.350
LRFN2	LRFN4	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): LRFN2 (Affinity Capture-RNA), LRFN4 (Affinity Capture-MS), LRFN2 (Affinity Capture-MS), LRFN2 (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), LRFN2 (Two-hybrid), LRFN2 (Cross-Linking-MS (XL-MS)), LRFN2 (Affinity Capture-RNA), LRFN2 (Affinity Capture-MS)

ESM2 similar proteins: A1XQX1, A1XQX3, A1XQY0, A8WGA3, C6K2K4, D0PRN2, D0PRN4, D4A1J9, E9PUN2, O13097, O42596, O73612, O73874, P0DI97, P52795, P52796, P58400, P58401, P98172, Q01974, Q0PMD2, Q17QD6, Q28142, Q28143, Q460M5, Q63373, Q63376, Q6NW40, Q6PCX7, Q6PFE7, Q7TQ33, Q80TG9, Q8BNJ6, Q8BXA0, Q8C985, Q8IYR6, Q8NC67, Q91590, Q96B86, Q96NI6

Diamond homologs: A0A1Y9G8H0, A0A452E9Y6, A1KZ92, A2A8L5, A2AJ76, A4IFW2, A4IGL7, A4IIW9, A5JUY8, A7MBJ4, A8WGA3, A8WQH2, B0BNK7, B3A0P3, D2HFT7, D3YXG0, D4A1J9, D4ABX8, G5EBF1, G5EG78, H2A0M7, O15146, O35158, O55005, O89026, P05164, P07202, P09933, P0C6S8, P0C7J6, P11247, P11678, P14650, P16621, P22079, P23468, P35419, P49290, P70193, P80025

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DLG4	“up-regulates activity”	LRFN2	binding
LRFN2	up-regulates	Neurite_outgrowth

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1418 predictions. Top by Δscore:

Variant	Effect	Δscore
6:40392908:TCATC:T	acceptor_gain	1.0000
6:40392909:CATCC:C	acceptor_gain	1.0000
6:40392910:ATC:A	acceptor_gain	1.0000
6:40392911:TC:T	acceptor_gain	1.0000
6:40392912:CC:C	acceptor_gain	1.0000
6:40392913:C:CA	acceptor_loss	1.0000
6:40392913:C:CC	acceptor_gain	1.0000
6:40433127:AGCGC:A	acceptor_gain	1.0000
6:40433128:GCGC:G	acceptor_gain	1.0000
6:40433129:CGC:C	acceptor_gain	1.0000
6:40433129:CGCC:C	acceptor_gain	1.0000
6:40433130:GC:G	acceptor_gain	1.0000
6:40433131:CC:C	acceptor_gain	1.0000
6:40433132:C:CC	acceptor_gain	1.0000
6:40433133:T:G	acceptor_loss	1.0000
6:40392909:CATC:C	acceptor_gain	0.9900
6:40433132:C:T	acceptor_gain	0.9900
6:40455918:AGC:A	donor_gain	0.9800
6:40586936:CTCA:C	donor_loss	0.9800
6:40586937:TCACC:T	donor_loss	0.9800
6:40586938:CAC:C	donor_loss	0.9800
6:40586939:A:T	donor_loss	0.9800
6:40586940:C:CG	donor_loss	0.9800
6:40392910:ATCCT:A	acceptor_gain	0.9700
6:40392911:TCCT:T	acceptor_gain	0.9700
6:40392913:C:T	acceptor_gain	0.9700
6:40392925:G:C	acceptor_gain	0.9700
6:40407741:C:CT	donor_gain	0.9700
6:40431713:C:CG	donor_loss	0.9700
6:40392912:CCT:C	acceptor_gain	0.9600

AlphaMissense

5129 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:40431794:C:A	W440C	1.000
6:40431794:C:G	W440C	1.000
6:40431796:A:G	W440R	1.000
6:40431796:A:T	W440R	1.000
6:40432037:G:C	C359W	1.000
6:40432038:C:T	C359Y	1.000
6:40432039:A:G	C359R	1.000
6:40432083:A:G	L344P	1.000
6:40432148:C:A	W322C	1.000
6:40432148:C:G	W322C	1.000
6:40432150:A:G	W322R	1.000
6:40432150:A:T	W322R	1.000
6:40432185:C:G	C310S	1.000
6:40432186:A:G	C310R	1.000
6:40432186:A:T	C310S	1.000
6:40432388:G:C	N242K	1.000
6:40432388:G:T	N242K	1.000
6:40432493:A:C	N207K	1.000
6:40432493:A:T	N207K	1.000
6:40432565:G:C	N183K	1.000
6:40432565:G:T	N183K	1.000
6:40432637:G:C	N159K	1.000
6:40432637:G:T	N159K	1.000
6:40432638:T:A	N159I	1.000
6:40432653:A:G	L154P	1.000
6:40432712:G:C	N134K	1.000
6:40432712:G:T	N134K	1.000
6:40432728:A:G	L129P	1.000
6:40432784:A:C	N110K	1.000
6:40432784:A:T	N110K	1.000

dbSNP variants (sampled 300 via entrez): RS1000002099 (6:40424579 C>T), RS1000002458 (6:40399415 CTTTT>C), RS1000002717 (6:40497002 G>A), RS1000017873 (6:40578032 C>A,T), RS1000056896 (6:40419601 A>G), RS1000084304 (6:40461335 G>C), RS1000084971 (6:40522232 A>C), RS1000085564 (6:40548346 C>T), RS1000095468 (6:40399085 A>G), RS1000114807 (6:40577101 T>A,C), RS1000116597 (6:40548179 C>T), RS1000166124 (6:40441168 G>A), RS1000172821 (6:40554760 C>G,T), RS1000179249 (6:40585947 C>T), RS1000181756 (6:40518046 C>T)

Disease associations

OMIM: gene MIM:612808 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST001718_2	Multiple cancers (lung cancer, gastric cancer, and squamous cell carcinoma)	2.000000e-06
GCST001718_3	Multiple cancers (lung cancer, gastric cancer, and squamous cell carcinoma)	5.000000e-09
GCST001718_4	Multiple cancers (lung cancer, gastric cancer, and squamous cell carcinoma)	1.000000e-12
GCST001762_524	Obesity-related traits	8.000000e-06
GCST001762_653	Obesity-related traits	3.000000e-06
GCST002283_3	Amyotrophic lateral sclerosis (sporadic)	9.000000e-09
GCST003431_2	Incident coronary heart disease	2.000000e-06
GCST004065_16	Waist circumference	6.000000e-06
GCST004065_17	Waist circumference	2.000000e-08
GCST004557_55	Body mass index	8.000000e-08
GCST004558_239	Body mass index (joint analysis main effects and physical activity interaction)	3.000000e-08
GCST004559_125	Body mass index in physically active individuals	2.000000e-06
GCST004559_167	Body mass index in physically active individuals	2.000000e-08
GCST004766_9	Triglyceride change in response to fenofibrate in statin-treated type 2 diabetes	2.000000e-08
GCST004904_74	Body mass index	7.000000e-10
GCST005830_54	Hand grip strength	1.000000e-08
GCST006979_278	Heel bone mineral density	2.000000e-09
GCST007324_17	Adventurousness	2.000000e-09
GCST007325_92	General risk tolerance (MTAG)	1.000000e-10
GCST008155_77	Waist-hip ratio	5.000000e-06
GCST008159_27	Waist-to-hip ratio adjusted for BMI	6.000000e-06
GCST009379_50	Type 2 diabetes	9.000000e-10
GCST010988_361	Adult body size	4.000000e-20
GCST011743_42	HDL cholesterol levels in HIV infection	3.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0007681	triglyceride change measurement
EFO:0006941	grip strength measurement
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0004343	waist-hip ratio
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Calcitriol	decreases expression, affects cotreatment	1
Estradiol	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

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