SESTD1

Summary

SESTD1 (SEC14 and spectrin domain containing 1, HGNC:18379) is a protein-coding gene on chromosome 2q31.2, encoding SEC14 domain and spectrin repeat-containing protein 1 (Q86VW0). May act as the primary docking protein directing membrane turnover and assembly of the transient receptor potential channels TRPC4 and TRPC5.

Enables phosphatidylinositol-3,4-bisphosphate binding activity and phospholipid binding activity. Involved in negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel. Located in calcium channel complex and intermediate filament cytoskeleton.

Source: NCBI Gene 91404 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 83 total
• MANE Select transcript: NM_178123

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18379
Approved symbol	SESTD1
Name	SEC14 and spectrin domain containing 1
Location	2q31.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434O0515, Solo
Ensembl gene	ENSG00000187231
Ensembl biotype	protein_coding
OMIM	621011
Entrez	91404

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000335289, ENST00000426988, ENST00000428443, ENST00000435047, ENST00000440010, ENST00000446758, ENST00000452991, ENST00000486468, ENST00000489901, ENST00000854635, ENST00000854636, ENST00000854637, ENST00000854638, ENST00000854639, ENST00000854640, ENST00000932265, ENST00000949561, ENST00000949562, ENST00000949563, ENST00000949564, ENST00000949565, ENST00000949566, ENST00000949567

RefSeq mRNA: 1 — MANE Select: NM_178123 NM_178123

CCDS: CCDS33338

Canonical transcript exons

ENST00000428443 — 18 exons

Exon	Start	End
ENSE00001340622	179123715	179123829
ENSE00001340625	179124364	179124558
ENSE00001340627	179132304	179132426
ENSE00001340630	179146402	179146457
ENSE00001340631	179149297	179149394
ENSE00001340633	179151278	179151391
ENSE00001836148	179101678	179110028
ENSE00001892961	179264499	179264832
ENSE00003463616	179115065	179115256
ENSE00003480444	179116668	179116790
ENSE00003568457	179117532	179117613
ENSE00003598616	179191787	179191866
ENSE00003629122	179176448	179176538
ENSE00003636098	179112724	179112845
ENSE00003637901	179143592	179143803
ENSE00003640049	179172120	179172233
ENSE00003661111	179183080	179183188
ENSE00003661247	179121770	179121929

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 97.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.8033 / max 461.1191, expressed in 1757 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32673	12.2221	1715
32669	7.4117	1638
32675	1.2693	139
32672	0.3607	157
32670	0.3576	148
32674	0.1095	40
32671	0.0725	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.91	gold quality
corpus callosum	UBERON:0002336	97.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.14	gold quality
mucosa of stomach	UBERON:0001199	96.74	gold quality
inferior vagus X ganglion	UBERON:0005363	96.50	gold quality
subthalamic nucleus	UBERON:0001906	96.42	gold quality
cartilage tissue	UBERON:0002418	96.23	gold quality
kidney epithelium	UBERON:0004819	95.95	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.92	gold quality
secondary oocyte	CL:0000655	95.80	gold quality
nasal cavity epithelium	UBERON:0005384	95.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.32	gold quality
tendon	UBERON:0000043	95.18	gold quality
pancreatic ductal cell	CL:0002079	95.11	gold quality
descending thoracic aorta	UBERON:0002345	95.02	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.94	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.94	gold quality
popliteal artery	UBERON:0002250	94.85	gold quality
spinal cord	UBERON:0002240	94.84	gold quality
tibial artery	UBERON:0007610	94.83	gold quality
globus pallidus	UBERON:0001875	94.80	gold quality
sural nerve	UBERON:0015488	94.75	gold quality
medial globus pallidus	UBERON:0002477	94.74	gold quality
islet of Langerhans	UBERON:0000006	94.71	gold quality
aorta	UBERON:0000947	94.65	gold quality
lateral globus pallidus	UBERON:0002476	94.57	gold quality
saphenous vein	UBERON:0007318	94.49	gold quality
adipose tissue	UBERON:0001013	94.45	gold quality
thoracic aorta	UBERON:0001515	94.40	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.17
E-GEOD-137537	yes	5.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

394 targeting SESTD1, 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-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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-433-3P	99.98	69.37	1203
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-367-3P	99.98	74.83	1819

Literature-anchored findings (GeneRIF, showing 4)

• SESTD1 was found to associate with TRPC4 and TRPC5 via the channel’s calmodulin- and inositol 1,4,5-trisphosphate receptor-binding domain. (PMID:20164195)
• Upregulation of miR-532-5p and subsequent suppression of the SESTD1 and TAB3 genes represent an antiviral response aimed at limiting West Nile virus infection. (PMID:26676784)
• The interplay between Solo protein and keratin 8/keratin 18 filaments plays a crucial role in tensile force-induced RhoA activation and consequent actin cytoskeletal reinforcement in endothelial cells. (PMID:26823019)
• Solo plays a crucial role in HD formation and acinar development in epithelial cells by regulating mechanical force-induced RhoA activation and keratin filament organization. (PMID:29672603)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sestd1	ENSDARG00000040614
mus_musculus	Sestd1	ENSMUSG00000042272
rattus_norvegicus	Sestd1	ENSRNOG00000012603

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), KALRN (ENSG00000160145), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

SEC14 domain and spectrin repeat-containing protein 1 — Q86VW0 (reviewed: Q86VW0)

Alternative names: Huntingtin-interacting protein-like protein, Protein Solo

All UniProt accessions (5): C9J4X8, C9JHW6, Q86VW0, H0Y774, H7BXT9

UniProt curated annotations — full annotation on UniProt →

Function. May act as the primary docking protein directing membrane turnover and assembly of the transient receptor potential channels TRPC4 and TRPC5. Binds phospholipids such as phosphatidylinositol monophosphates, phosphatidylinositol diphosphates (PIP2s) and phosphatidic acid, but not less polar lipids including phosphatidylcholine, phosphatidylserine, and phosphatidylinositol. The binding to PIP2s is calcium dependent. Might be involved in the plasma membrane localization of CTNNB1.

Subunit / interactions. Interacts (via the spectrin 1 repeat) with TRPC4 and TRPC5 (via CIRB domain). Interacts with CTNNB1.

Tissue specificity. Broad expression. High expression in thalamus and brain. Significantly expressed in vasculature.

Miscellaneous. Called SOLO because the encoded protein is related to but shorter than DUO and TRIO.

Similarity. Belongs to the SOLO family.

RefSeq proteins (1): NP_835224* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001251	CRAL-TRIO_dom	Domain
IPR056804	Spectrin_SESTD1	Domain

Pfam: PF13716, PF24915

UniProt features (8 total): repeat 3, sequence variant 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86VW0-F1	86.06	0.58

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 285 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, TTTGTAG_MIR520D, GOBP_MONOATOMIC_CATION_TRANSPORT, PATIL_LIVER_CANCER, GTGCCTT_MIR506, GGGCATT_MIR365, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, CATTTCA_MIR203, FREAC3_01, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, LIAO_METASTASIS, GOBP_NEGATIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT

GO Biological Process (1): negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel (GO:1904878)

GO Molecular Function (8): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol-5-phosphate binding (GO:0010314), phosphatidylinositol-3-phosphate binding (GO:0032266), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), phosphatidylinositol-4-phosphate binding (GO:0070273), phosphatidic acid binding (GO:0070300), phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), protein binding (GO:0005515)

GO Cellular Component (2): intermediate filament cytoskeleton (GO:0045111), calcium channel complex (GO:0034704)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol phosphate binding	5
phosphatidylinositol bisphosphate binding	3
anion binding	3
calcium ion transmembrane transport via high voltage-gated calcium channel	1
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1
negative regulation of calcium ion transmembrane transport	1
phospholipid binding	1
binding	1
cytoskeleton	1
cation channel complex	1

Protein interactions and networks

STRING

600 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SESTD1	TRPC5	Q9UL62	816
SESTD1	TRPC4	Q9UBN4	805
SESTD1	TAB3	Q8N5C8	544
SESTD1	SMC3	Q9UQE7	507
SESTD1	PLEK	P08567	502
SESTD1	PLEK2	Q9NYT0	497
SESTD1	BRCA1	P38398	479
SESTD1	PARP1	P09874	476
SESTD1	CALML6	Q8TD86	455
SESTD1	CALML3	P27482	455
SESTD1	CALML5	Q9NZT1	455
SESTD1	CALML4	Q96GE6	455
SESTD1	CALM1	P02593	454
SESTD1	A0A2R8Y809	A0A2R8Y809	446
SESTD1	TBCE	Q15813	446

IntAct

82 interactions, top by confidence:

A	B	Type	Score
GPS2	SESTD1	psi-mi:“MI:0915”(physical association)	0.780
SESTD1	GPS2	psi-mi:“MI:0915”(physical association)	0.780
SESTD1	STMN2	psi-mi:“MI:0915”(physical association)	0.670
FAM9C	NDC80	psi-mi:“MI:0914”(association)	0.670
P4HA3	FAM171A2	psi-mi:“MI:0914”(association)	0.640
IRAK2	SESTD1	psi-mi:“MI:0914”(association)	0.640
SESTD1	STMN1	psi-mi:“MI:0915”(physical association)	0.560
STMN1	SESTD1	psi-mi:“MI:0915”(physical association)	0.560
SESTD1	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
IQCB1	SESTD1	psi-mi:“MI:0915”(physical association)	0.560
DACT3	SESTD1	psi-mi:“MI:0915”(physical association)	0.560
SESTD1	ZNF830	psi-mi:“MI:0915”(physical association)	0.560
SESTD1	HSF4	psi-mi:“MI:0915”(physical association)	0.560
TEAD4	SESTD1	psi-mi:“MI:0915”(physical association)	0.560
SESTD1	CBX8	psi-mi:“MI:0915”(physical association)	0.560
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
HSF4	HSF1	psi-mi:“MI:0914”(association)	0.530
ARL11	SESTD1	psi-mi:“MI:0914”(association)	0.530
STMN2	MTA2	psi-mi:“MI:0914”(association)	0.530

BioGRID (56): SESTD1 (Two-hybrid), SESTD1 (Two-hybrid), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS), SESTD1 (Affinity Capture-MS)

ESM2 similar proteins: A2AGL3, B0LPN4, E9PZQ0, E9Q401, F1LMY4, F1Q8X5, P0C7A6, P11716, P11881, P16960, P21817, P29994, P29995, P30957, P42694, P48553, Q0VEJ0, Q14571, Q14643, Q15413, Q1LVW0, Q24498, Q28C34, Q3TLI0, Q5F361, Q5RCP7, Q6NRC7, Q6NRD0, Q6NYU2, Q6QI06, Q6R327, Q7SXV1, Q7Z3V4, Q7ZUV0, Q7ZYD9, Q80UK0, Q86VW0, Q8BHL5, Q8BIK4, Q8BWW9

Diamond homologs: A2CG49, A8DYP0, F1M0Z1, O15068, O60229, O75962, P10911, P97924, Q0KL02, Q13009, Q14155, Q1LUA6, Q58EX7, Q5M7P4, Q60610, Q63406, Q64096, Q6GNM9, Q6GPX2, Q6KAU7, Q6P720, Q6XZF7, Q6ZPF3, Q7SX85, Q80U35, Q80UK0, Q86VW0, Q86VW2, Q86YR7, Q8IVF5, Q96PE2, Q96PX9, Q9CWR0, Q9H7P9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

4039 predictions. Top by Δscore:

Variant	Effect	Δscore
2:179112718:CCATA:C	donor_loss	1.0000
2:179112719:CATAC:C	donor_loss	1.0000
2:179112721:TACCC:T	donor_loss	1.0000
2:179112722:A:T	donor_loss	1.0000
2:179112722:AC:A	donor_gain	1.0000
2:179112723:CC:C	donor_gain	1.0000
2:179112723:CCCAT:C	donor_gain	1.0000
2:179112727:T:C	donor_gain	1.0000
2:179112737:C:CT	donor_gain	1.0000
2:179112738:T:TT	donor_gain	1.0000
2:179112739:A:AC	donor_gain	1.0000
2:179112740:C:CC	donor_gain	1.0000
2:179112775:A:C	donor_gain	1.0000
2:179112842:AAAT:A	acceptor_gain	1.0000
2:179112844:AT:A	acceptor_gain	1.0000
2:179112846:C:CA	acceptor_loss	1.0000
2:179112846:C:CC	acceptor_gain	1.0000
2:179112847:T:G	acceptor_loss	1.0000
2:179115147:A:AC	donor_gain	1.0000
2:179115148:C:CC	donor_gain	1.0000
2:179115148:CT:C	donor_gain	1.0000
2:179116712:T:A	donor_gain	1.0000
2:179116787:CTGC:C	acceptor_gain	1.0000
2:179117526:CCTTA:C	donor_loss	1.0000
2:179117527:CTTAC:C	donor_loss	1.0000
2:179117528:TTAC:T	donor_loss	1.0000
2:179117529:TA:T	donor_loss	1.0000
2:179117531:C:CG	donor_loss	1.0000
2:179117609:CACAT:C	acceptor_gain	1.0000
2:179117611:CAT:C	acceptor_gain	1.0000

AlphaMissense

4582 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:179115156:A:G	L583P	1.000
2:179115240:C:T	G555D	1.000
2:179115241:C:G	G555R	1.000
2:179116768:A:G	L516P	1.000
2:179116777:A:G	L513P	1.000
2:179116779:C:A	W512C	1.000
2:179116779:C:G	W512C	1.000
2:179116781:A:G	W512R	1.000
2:179116781:A:T	W512R	1.000
2:179124422:A:G	L370P	1.000
2:179124455:A:G	L359P	1.000
2:179124533:A:G	L333P	1.000
2:179143680:A:G	L254P	1.000
2:179143803:C:T	G213E	1.000
2:179146402:C:A	G213W	1.000
2:179146402:C:G	G213R	1.000
2:179146402:C:T	G213R	1.000
2:179149348:A:G	L177P	1.000
2:179149380:A:C	F166L	1.000
2:179149380:A:T	F166L	1.000
2:179149381:A:G	F166S	1.000
2:179149382:A:G	F166L	1.000
2:179151293:C:A	W156C	1.000
2:179151293:C:G	W156C	1.000
2:179151295:A:G	W156R	1.000
2:179151295:A:T	W156R	1.000
2:179151321:C:T	G147E	1.000
2:179151339:A:G	L141S	1.000
2:179151366:A:C	L132W	1.000
2:179151366:A:G	L132S	1.000

dbSNP variants (sampled 300 via entrez): RS1000016803 (2:179130259 T>C), RS1000029501 (2:179185389 T>C), RS1000033542 (2:179219177 C>T), RS1000092106 (2:179163967 A>G), RS1000107596 (2:179184043 A>G), RS1000125204 (2:179123489 A>G), RS1000141624 (2:179184877 G>A), RS1000154018 (2:179130318 A>C,G), RS1000187913 (2:179147715 C>A), RS1000215131 (2:179200598 A>C,G), RS1000216833 (2:179226451 T>A,C), RS1000297574 (2:179225180 G>A), RS1000323090 (2:179225933 G>A), RS1000324970 (2:179157751 AATTT>A), RS1000337163 (2:179151891 A>G)

Disease associations

OMIM: gene MIM:621011 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001872_11	Presence of antiphospholipid antibodies	6.000000e-06
GCST003159_2	Objective response to lithium treatment	3.000000e-08
GCST003815_19	Late-onset Alzheimer’s disease	2.000000e-06
GCST005557_6	Serum uric acid levels	6.000000e-07
GCST009462_39	Optic disc size	6.000000e-09
GCST010002_405	Refractive error	1.000000e-70

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001870	late-onset Alzheimers disease
EFO:0004761	uric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	3
Cyclosporine	decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
trichostatin A	affects cotreatment, decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects 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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Cadmium	increases abundance, increases expression	1
Demecolcine	decreases expression	1
Ketoconazole	increases expression	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	increases expression	1

Clinical trials (associated diseases)

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