SVIL

Summary

SVIL (supervillin, HGNC:11480) is a protein-coding gene on chromosome 10p11.23, encoding Supervillin (O95425). Forms a high-affinity link between the actin cytoskeleton and the membrane.

This gene encodes a bipartite protein with distinct amino- and carboxy-terminal domains. The amino-terminus contains nuclear localization signals and the carboxy-terminus contains numerous consecutive sequences with extensive similarity to proteins in the gelsolin family of actin-binding proteins, which cap, nucleate, and/or sever actin filaments. The gene product is tightly associated with both actin filaments and plasma membranes, suggesting a role as a high-affinity link between the actin cytoskeleton and the membrane. The encoded protein appears to aid in both myosin II assembly during cell spreading and disassembly of focal adhesions. Several transcript variants encoding different isoforms of supervillin have been described.

Source: NCBI Gene 6840 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myofibrillar myopathy 10 (Strong, GenCC)
• GWAS associations: 13
• Clinical variants (ClinVar): 575 total — 2 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_021738

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11480
Approved symbol	SVIL
Name	supervillin
Location	10p11.23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197321
Ensembl biotype	protein_coding
OMIM	604126
Entrez	6840

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 38 protein_coding, 6 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000355867, ENST00000375398, ENST00000375400, ENST00000460007, ENST00000464726, ENST00000464984, ENST00000474106, ENST00000482607, ENST00000483758, ENST00000490031, ENST00000491872, ENST00000632315, ENST00000674242, ENST00000674350, ENST00000674475, ENST00000674490, ENST00000860287, ENST00000860288, ENST00000860289, ENST00000860290, ENST00000860291, ENST00000860292, ENST00000860293, ENST00000860294, ENST00000860295, ENST00000860296, ENST00000860297, ENST00000860298, ENST00000860299, ENST00000860300, ENST00000924353, ENST00000924354, ENST00000924355, ENST00000924356, ENST00000924357, ENST00000946670, ENST00000946671, ENST00000946672, ENST00000946673, ENST00000946674, ENST00000946675, ENST00000946676, ENST00000946677, ENST00000946678, ENST00000946679, ENST00000946680, ENST00000946681

RefSeq mRNA: 4 — MANE Select: NM_021738 NM_001323599, NM_001323600, NM_003174, NM_021738

CCDS: CCDS7163, CCDS7164, CCDS91234

Canonical transcript exons

ENST00000355867 — 38 exons

Exon	Start	End
ENSE00000816339	29471138	29471243
ENSE00000816342	29480537	29480813
ENSE00000985781	29522410	29522635
ENSE00001407651	29569255	29569312
ENSE00001426990	29563201	29563292
ENSE00001946837	29457338	29458333
ENSE00002449286	29529705	29529844
ENSE00002453120	29554783	29554934
ENSE00002456809	29535989	29536069
ENSE00002480659	29532002	29532172
ENSE00002482208	29523451	29524027
ENSE00002486323	29532529	29533458
ENSE00002488043	29524472	29524715
ENSE00002489458	29550597	29551263
ENSE00002493761	29531254	29531288
ENSE00002497276	29530607	29530668
ENSE00002497441	29526961	29527056
ENSE00002704111	29555051	29555108
ENSE00003240590	29486410	29486557
ENSE00003261011	29484656	29484831
ENSE00003265638	29467742	29467875
ENSE00003279631	29463492	29463635
ENSE00003283176	29458434	29458589
ENSE00003290610	29487163	29487299
ENSE00003329686	29486085	29486230
ENSE00003350206	29481584	29481728
ENSE00003417605	29470276	29470483
ENSE00003431747	29465595	29465750
ENSE00003446842	29488601	29488756
ENSE00003454616	29462277	29462401
ENSE00003463755	29495092	29495181
ENSE00003466743	29473838	29473989
ENSE00003495036	29493214	29493391
ENSE00003551785	29499116	29499263
ENSE00003585459	29490847	29491019
ENSE00003613193	29494914	29495000
ENSE00003665036	29512735	29512861
ENSE00003936366	29634420	29634971

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 99.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.7388 / max 1386.8346, expressed in 1690 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108886	7.1275	1180
108875	6.2837	660
108885	4.4746	1288
108888	4.3725	1291
108884	3.6676	1201
108883	1.6400	779
108887	1.4341	738
108872	0.9229	211
108873	0.6817	219
108889	0.4414	240

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	99.67	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.56	gold quality
vastus lateralis	UBERON:0001379	99.50	gold quality
biceps brachii	UBERON:0001507	99.50	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.44	gold quality
deltoid	UBERON:0001476	99.41	gold quality
gastrocnemius	UBERON:0001388	99.39	gold quality
skeletal muscle tissue	UBERON:0001134	99.35	gold quality
muscle of leg	UBERON:0001383	99.32	gold quality
tibialis anterior	UBERON:0001385	99.31	gold quality
muscle organ	UBERON:0001630	99.31	gold quality
diaphragm	UBERON:0001103	99.30	gold quality
body of tongue	UBERON:0011876	99.26	gold quality
quadriceps femoris	UBERON:0001377	99.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.16	gold quality
triceps brachii	UBERON:0001509	99.08	gold quality
saphenous vein	UBERON:0007318	99.02	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.89	gold quality
lower esophagus	UBERON:0013473	98.88	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.87	gold quality
muscle tissue	UBERON:0002385	98.83	gold quality
mucosa of stomach	UBERON:0001199	98.80	gold quality
blood vessel layer	UBERON:0004797	98.77	gold quality
left ventricle myocardium	UBERON:0006566	98.59	gold quality
heart right ventricle	UBERON:0002080	98.58	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.56	gold quality
right coronary artery	UBERON:0001625	98.54	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.47	gold quality
myocardium	UBERON:0002349	98.24	gold quality
cauda epididymis	UBERON:0004360	98.24	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	71.53
E-HCAD-10	yes	27.81
E-MTAB-5061	yes	25.85
E-GEOD-81547	yes	22.92
E-GEOD-83139	yes	10.84
E-HCAD-35	yes	9.64
E-ENAD-27	yes	6.44
E-ANND-2	no	1991.59
E-GEOD-81383	no	1196.07
E-MTAB-4850	no	97.65
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3

miRNA regulators (miRDB)

72 targeting SVIL, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-548AI	99.69	69.24	1494

Literature-anchored findings (GeneRIF, showing 19)

• Supervillin associates with androgen receptor and modulates its transcriptional activity. (PMID:11792840)
• archvillin is among the first costameric proteins to assemble during myogenesis and that it contributes to myogenic membrane structure and differentiation. (PMID:12711699)
• These data suggest a model in which archvillin attaches directly to the Z-line of skeletal muscle through an interaction with the nebulin C-terminus. (PMID:18639526)
• SV is a component of podosomes and invadopodia and SV plays a role in invadopodial function, perhaps as a mediator of cortactin localization, activation state, and/or dynamics of metalloproteinases at the ventral cell surface. (PMID:19109420)
• The first NMR solution structure and (15)N-relaxation analysis of a villin-type headpiece domain natively devoid of F-actin binding activity, that of supervillin headpiece (SVHP), is shown. (PMID:19683541)
• Supervillin, like its interactors, is important for efficient cytokinesis. (PMID:20309963)
• supervillin, F-actin and associated proteins coordinate a rapid, basolateral membrane recycling pathway that contributes to ERK signaling and actin-based cell motility (PMID:20331534)
• supervillin is a novel molecule that associates with KIR2DL1 receptor and regulates the inhibitory signaling in NK cells. (PMID:21070852)
• Human genome-wide association and mouse knockout approaches identify platelet supervillin as an inhibitor of thrombus formation under shear stress. (PMID:22550155)
• adhesion regulatory protein supervillin increases cell survival by decreasing levels of the tumor suppressor protein p53 and downstream target genes (PMID:23382381)
• An actin/myosin-II-binding protein, supervillin (SVIL), is a substrate of PLK1. (PMID:23750008)
• Supervillin concentrates activated and total myosin II at the furrow, and simultaneous knockdown of supervillin and anillin additively increases cell division failure. (PMID:24088567)
• These results position archvillin as a mechanically sensitive component of the dystrophin complex and demonstrate that signaling defects caused by loss of gamma-SG occur both at the sarcolemma and in the nucleus. (PMID:25605665)
• SVIL regulates neuronal maturation by controlling LSD1+8a mediated histone H3K9 demethylation. (PMID:25684206)
• Supervillin promotes tumor angiogenesis in liver cancer. (PMID:32468064)
• A twinpair analysis indicates congenital scoliosis is associated with allelespecific methylation in the SVIL gene. (PMID:32582973)
• Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles. (PMID:32779703)
• Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis. (PMID:33862101)
• Supervillin Contributes to LPS-induced Inflammatory Response in THP-1 Cell-derived Macrophages. (PMID:34480249)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	svilb	ENSDARG00000014651
danio_rerio	svila	ENSDARG00000055075
danio_rerio		ENSDARG00000110291
mus_musculus	Svil	ENSMUSG00000024236
rattus_norvegicus	Svil	ENSRNOG00000018110
drosophila_melanogaster	Gel	FBGN0010225
caenorhabditis_elegans		WBGENE00010593

Paralogs (7): SCIN (ENSG00000006747), CAPG (ENSG00000042493), VIL1 (ENSG00000127831), AVIL (ENSG00000135407), VILL (ENSG00000136059), GSN (ENSG00000148180), FLII (ENSG00000177731)

Protein

Protein identifiers

Supervillin — O95425 (reviewed: O95425)

Alternative names: Archvillin, p205/p250

All UniProt accessions (4): A0A0J9YWY6, A0A6I8PIX7, A0A6I8PL75, O95425

UniProt curated annotations — full annotation on UniProt →

Function. Forms a high-affinity link between the actin cytoskeleton and the membrane. Is among the first costameric proteins to assemble during myogenesis and it contributes to myogenic membrane structure and differentiation. Appears to be involved in myosin II assembly. May modulate myosin II regulation through MLCK during cell spreading, an initial step in cell migration. May play a role in invadopodial function. In addition to its cytoskeletal activities, acts as a cofactor or scaffold for KDM1A, facilitating H3K9me2 demethylation and promoting gene activation, especially in neuronal contexts. May be involved in modulation of focal adhesions. Supervillin-mediated down-regulation of focal adhesions involves binding to TRIP6. Plays a role in cytokinesis through KIF14 interaction.

Subunit / interactions. Associates with F-actin. Interacts with NEB. Interacts with MYH9. Interacts with MYLK. Interacts with TASOR. Interacts with KDM1A (isoforms 2 and 4); this interaction recruits and stabilizes isoforms 2 and 4 facilitating their H3K9me2 demethylation. Interacts with TRIP6. Interacts with DYNLT1. Interacts with KIF14; at midbody during cytokinesis.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton. Cell projection. Invadopodium. Podosome. Midbody. Cleavage furrow.

Tissue specificity. Expressed in many tissues. Most abundant in muscle, bone marrow, thyroid gland and salivary gland. Isoform 1 (archvillin) is muscle specific.

Disease relevance. Myopathy, myofibrillar, 10 (MFM10) [MIM:619040] A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM10 is an autosomal recessive disorder characterized by muscle pain, cramping, exercise fatigue, and progressive muscle rigidity. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. As opposed to other villin-type headpiece domains, supervillin HP (SVHP) doesn’t bind F-actin due to the absence of a conformationally flexible region (V-loop).

Similarity. Belongs to the villin/gelsolin family.

Isoforms (4)

UniProt ID	Names	Canonical?
O95425-1	1, Archvillin, p250, SV2	yes
O95425-2	2, Supervillin, p205, SV1
O95425-3	SV3
O95425-4	SV4

RefSeq proteins (4): NP_001310528, NP_001310529, NP_003165, NP_068506* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003128	Villin_headpiece	Domain
IPR007122	Villin/Gelsolin	Family
IPR007123	Gelsolin-like_dom	Domain
IPR029006	ADF-H/Gelsolin-like_dom_sf	Homologous_superfamily
IPR036886	Villin_headpiece_dom_sf	Homologous_superfamily

Pfam: PF00626, PF02209

UniProt features (81 total): modified residue 32, compositionally biased region 13, region of interest 10, sequence variant 8, repeat 5, helix 5, splice variant 3, strand 2, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2K6M	SOLUTION NMR
2K6N	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95425-F1	53.95	0.20

Functional residue map

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

Post-translational modifications (32): 50, 221, 238, 240, 245, 253, 259, 270, 319, 673, 707, 769, 850, 852, 914, 920, 924, 968, 1000, 1052 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
2176	strongly increased affinity for f-actin.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 447 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, MODULE_52, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, WANG_CLIM2_TARGETS_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GCANCTGNY_MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, TOMLINS_PROSTATE_CANCER_DN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5

GO Biological Process (7): skeletal muscle tissue development (GO:0007519), actin polymerization or depolymerization (GO:0008154), positive regulation of cytokinesis (GO:0032467), actin filament severing (GO:0051014), barbed-end actin filament capping (GO:0051016), cytoskeleton organization (GO:0007010), muscle structure development (GO:0061061)

GO Molecular Function (4): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (15): podosome (GO:0002102), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), midbody (GO:0030496), cleavage furrow (GO:0032154), microtubule minus-end (GO:0036449), cell projection (GO:0042995), costamere (GO:0043034), cytoskeleton (GO:0005856), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
striated muscle tissue development	1
skeletal muscle organ development	1
actin filament organization	1
cytokinesis	1
regulation of cytokinesis	1
positive regulation of cell division	1
positive regulation of cell cycle process	1
actin filament-based process	1
actin filament capping	1
organelle organization	1
anatomical structure development	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
binding	1
actin-based cell projection	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
cell-substrate junction	1
cytoskeleton	1
cell division site	1
plasma membrane region	1
microtubule end	1
myofibril	1
intracellular membraneless organelle	1
cell junction	1

Protein interactions and networks

STRING

1258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SVIL	CTTN	Q14247	704
SVIL	HCLS1	P14317	693
SVIL	KIF14	Q15058	589
SVIL	AR	P10275	581
SVIL	FMNL1	O95466	577
SVIL	ACTB	P02570	535
SVIL	KDM1A	O60341	524
SVIL	ACTC1	P04270	499
SVIL	FSCN1	Q16658	497
SVIL	CDKN1B	P46527	495
SVIL	INF2	Q27J81	489
SVIL	ITGB2	P05107	479
SVIL	NEB	P20929	468
SVIL	MYOD1	P15172	457
SVIL	SPHK1	Q9NYA1	446

IntAct

168 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
NEB	SVIL	psi-mi:“MI:0915”(physical association)	0.540
SVIL	NEB	psi-mi:“MI:0915”(physical association)	0.540
NEB	SVIL	psi-mi:“MI:0403”(colocalization)	0.540
DAPK1	SVIL	psi-mi:“MI:0914”(association)	0.530
CENPE	CLASP2	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
DBN1	SVIL	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
FOS	MYO1C	psi-mi:“MI:2364”(proximity)	0.480
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
SVIL	GAPDH	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (302): SVIL (Reconstituted Complex), USP7 (Reconstituted Complex), SVIL (Affinity Capture-Western), SVIL (Affinity Capture-MS), SVIL (Affinity Capture-MS), SVIL (Affinity Capture-MS), SVIL (Affinity Capture-MS), SVIL (Synthetic Growth Defect), SVIL (Affinity Capture-MS), SVIL (Proximity Label-MS), SVIL (Proximity Label-MS), SVIL (Affinity Capture-MS), SVIL (Affinity Capture-MS), SVIL (Affinity Capture-MS), SVIL (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTU1, A2AUY4, B7ZS37, D3Z8Y2, D4A4L4, D4A666, E1B7L7, O46385, O60293, O75152, O95425, P0DQW0, Q08AZ1, Q3KQW7, Q3U1C4, Q3UH68, Q3ZC82, Q4G0F8, Q4V9H5, Q5F3Z9, Q5NBX1, Q5REG6, Q5ZJJ1, Q5ZM88, Q61464, Q62394, Q68FE9, Q6NZF1, Q6PJT7, Q6ZQ03, Q6ZU65, Q76L83, Q7TMD5, Q8BHZ4, Q8BJ05, Q8BLG0, Q8BZ32, Q8C9B9, Q8CCJ9, Q8K298

Diamond homologs: O46385, O95425, P10733, Q8K4L3, Q08DM1, Q54K81

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLK1	“up-regulates activity”	SVIL	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	49.8×	3e-10
Activation of BAD and translocation to mitochondria	7	49.4×	4e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	43.5×	8e-09
RHO GTPases activate PKNs	11	32.3×	1e-11
Activation of BH3-only proteins	7	32.2×	9e-08
RHO GTPases activate PAKs	5	25.2×	4e-05
Intrinsic Pathway for Apoptosis	8	21.7×	1e-07
Striated Muscle Contraction	6	17.1×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	13.1×	7e-03
substantia nigra development	5	13.1×	7e-03
mitotic spindle assembly	5	12.3×	8e-03
actin filament organization	9	7.6×	1e-03
intracellular protein localization	10	7.5×	1e-03
actin cytoskeleton organization	11	6.2×	1e-03
cell division	12	4.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	6
Uncertain significance	345
Likely benign	40
Benign	126

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
981487	NM_021738.3(SVIL):c.4812C>A (p.Tyr1604Ter)	Pathogenic
981488	NM_021738.3(SVIL):c.3578_3579del (p.Val1193fs)	Pathogenic
2061785	NM_021738.3(SVIL):c.8+1G>A	Likely pathogenic
2062672	NM_021738.3(SVIL):c.5101-1G>A	Likely pathogenic
402169	NM_021738.3(SVIL):c.3626C>T (p.Ser1209Leu)	Likely pathogenic
4845670	NM_021738.3(SVIL):c.820C>T (p.Arg274Ter)	Likely pathogenic
4845896	NM_021738.3(SVIL):c.3164-2A>G	Likely pathogenic
4849290	NM_021738.3(SVIL):c.2065C>T (p.Arg689Ter)	Likely pathogenic

SpliceAI

6818 predictions. Top by Δscore:

Variant	Effect	Δscore
10:29458429:CTTA:C	donor_loss	1.0000
10:29458430:TTAC:T	donor_loss	1.0000
10:29458431:TA:T	donor_loss	1.0000
10:29458432:A:AC	donor_gain	1.0000
10:29458432:A:AT	donor_loss	1.0000
10:29458433:C:CA	donor_loss	1.0000
10:29458433:C:CC	donor_gain	1.0000
10:29458433:CCT:C	donor_gain	1.0000
10:29458586:TGTC:T	acceptor_gain	1.0000
10:29458587:GTC:G	acceptor_gain	1.0000
10:29458587:GTCC:G	acceptor_loss	1.0000
10:29458588:TC:T	acceptor_gain	1.0000
10:29458589:CC:C	acceptor_gain	1.0000
10:29458590:C:CC	acceptor_gain	1.0000
10:29462276:CCAT:C	donor_gain	1.0000
10:29463486:CCTCA:C	donor_loss	1.0000
10:29463487:CTCA:C	donor_loss	1.0000
10:29463488:TCA:T	donor_loss	1.0000
10:29463489:CA:C	donor_loss	1.0000
10:29463490:ACCTT:A	donor_loss	1.0000
10:29463491:C:A	donor_loss	1.0000
10:29463617:T:TC	acceptor_gain	1.0000
10:29465589:CCTTA:C	donor_loss	1.0000
10:29465590:CTTAC:C	donor_loss	1.0000
10:29465591:TTACC:T	donor_loss	1.0000
10:29465592:TACCT:T	donor_loss	1.0000
10:29465593:A:T	donor_loss	1.0000
10:29465594:C:CA	donor_loss	1.0000
10:29465594:CCTGG:C	donor_gain	1.0000
10:29465751:C:CC	acceptor_gain	1.0000

AlphaMissense

14500 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:29463597:A:G	W2058R	1.000
10:29463597:A:T	W2058R	1.000
10:29463599:A:G	L2057P	1.000
10:29470346:A:G	W1925R	1.000
10:29470346:A:T	W1925R	1.000
10:29481706:A:G	W1660R	1.000
10:29481706:A:T	W1660R	1.000
10:29484795:A:G	W1606R	1.000
10:29484795:A:T	W1606R	1.000
10:29458453:A:G	L2180P	0.999
10:29458507:A:G	L2162P	0.999
10:29462315:A:G	W2122R	0.999
10:29462315:A:T	W2122R	0.999
10:29462322:A:C	F2119L	0.999
10:29462322:A:T	F2119L	0.999
10:29462323:A:G	F2119S	0.999
10:29462324:A:G	F2119L	0.999
10:29462328:A:C	N2117K	0.999
10:29462328:A:T	N2117K	0.999
10:29462334:G:C	F2115L	0.999
10:29462334:G:T	F2115L	0.999
10:29462335:A:G	F2115S	0.999
10:29462336:A:G	F2115L	0.999
10:29462365:A:G	L2105P	0.999
10:29463530:C:G	R2080P	0.999
10:29463543:A:G	W2076R	0.999
10:29463543:A:T	W2076R	0.999
10:29463591:C:G	G2060R	0.999
10:29463595:C:A	W2058C	0.999
10:29463595:C:G	W2058C	0.999

dbSNP variants (sampled 300 via entrez): RS1000007732 (10:29551681 A>G), RS1000015949 (10:29736328 C>G,T), RS1000025214 (10:29731112 C>A,T), RS1000069989 (10:29615685 T>C), RS1000108060 (10:29536985 G>C), RS1000108574 (10:29649129 C>T), RS1000108834 (10:29583563 G>A), RS1000110640 (10:29689584 G>A), RS1000135288 (10:29460543 G>A), RS1000138657 (10:29505535 G>A), RS1000144445 (10:29644789 T>C), RS1000150235 (10:29466451 G>A), RS1000159875 (10:29700753 G>A), RS1000176445 (10:29584627 C>T), RS1000180492 (10:29679956 G>A)

Disease associations

OMIM: gene MIM:604126 | disease phenotypes: MIM:619040

GenCC curated gene-disease

Disease	Classification	Inheritance
myofibrillar myopathy 10	Strong	Autosomal recessive

Mondo (2): myofibrillar myopathy 10 (MONDO:0033620), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (1): Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

24 total (25 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000303	Mandibular prognathia
HP:0000475	Broad neck
HP:0001324	Muscle weakness
HP:0001712	Left ventricular hypertrophy
HP:0001852	Sandal gap
HP:0002808	Kyphosis
HP:0002987	Elbow flexion contracture
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003326	Myalgia
HP:0003394	Muscle spasm
HP:0003458	EMG: myopathic abnormalities
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0005184	Prolonged QTc interval
HP:0006380	Knee flexion contracture
HP:0006466	Ankle flexion contracture
HP:0010548	Percussion myotonia
HP:0011463	Childhood onset
HP:0012785	Flexion contracture of finger
HP:0025075	Increased QRS voltage
HP:0030973	Postexertional symptom exacerbation
HP:0410173	Increased circulating troponin I concentration
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000268_1	Normalized brain volume	8.000000e-06
GCST001501_1	Platelet thrombus formation	4.000000e-08
GCST002594_31	Neurofibrillary tangles	7.000000e-06
GCST004185_16	Lung function (FEV1/FVC)	8.000000e-11
GCST004403_1	Bone fracture in osteoporosis	4.000000e-08
GCST008058_48	Estimated glomerular filtration rate	3.000000e-10
GCST008059_203	Estimated glomerular filtration rate	4.000000e-09
GCST009391_1091	Metabolite levels	8.000000e-06
GCST009391_1750	Metabolite levels	9.000000e-07
GCST009439_3	Age-related cognitive decline (language) (slope of z-scores)	2.000000e-06
GCST011202_9	Dilated cardiomyopathy (MTAG)	2.000000e-09
GCST011210_4	Dilated cardiomyopathy	2.000000e-06
GCST90002400_700	Plateletcrit	3.000000e-12

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006797	neurofibrillary tangles measurement
EFO:0004713	FEV/FVC ratio
EFO:0010543	uridine diphosphate galactose measurement
EFO:0010544	uridine diphosphate glucose measurement
EFO:0010349	cholesteryl ester 20:5 measurement
EFO:0007710	cognitive decline measurement
EFO:0007985	platelet crit

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2368393	MIR604, SVIL		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	5
Estradiol	increases expression, increases reaction, affects expression, affects cotreatment, decreases expression	5
Acetaminophen	decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
arsenite	increases methylation, affects binding, decreases reaction	2
Fulvestrant	decreases expression, increases methylation	2
Air Pollutants	increases oxidation, affects expression, affects cotreatment, increases abundance	2
Benzo(a)pyrene	affects methylation	2
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
methylselenic acid	increases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, increases expression, affects cotreatment	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
afimoxifene	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
coumarin	affects phosphorylation	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.
NCT03832660	PHASE2	COMPLETED	Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
NCT04219826	PHASE2	COMPLETED	Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy
NCT04426578	PHASE2	UNKNOWN	Role of Perhexiline in Hypertrophic Cardiomyopathy