ANKRD1

Summary

ANKRD1 (ankyrin repeat domain 1, HGNC:15819) is a protein-coding gene on chromosome 10q23.31, encoding Ankyrin repeat domain-containing protein 1 (Q15327). May play an important role in endothelial cell activation.

The protein encoded by this gene is localized to the nucleus of endothelial cells and is induced by IL-1 and TNF-alpha stimulation. Studies in rat cardiomyocytes suggest that this gene functions as a transcription factor. Interactions between this protein and the sarcomeric proteins myopalladin and titin suggest that it may also be involved in the myofibrillar stretch-sensor system.

Source: NCBI Gene 27063 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial isolated dilated cardiomyopathy (Supportive, GenCC) — +5 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 577 total
• Phenotypes (HPO): 13
• MANE Select transcript: NM_014391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15819
Approved symbol	ANKRD1
Name	ankyrin repeat domain 1
Location	10q23.31
Locus type	gene with protein product
Status	Approved
Aliases	C-193, ALRP, CARP, CVARP, MCARP
Ensembl gene	ENSG00000148677
Ensembl biotype	protein_coding
OMIM	609599
Entrez	27063

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000371697, ENST00000869698, ENST00000869699, ENST00000945870, ENST00000945871

RefSeq mRNA: 1 — MANE Select: NM_014391 NM_014391

CCDS: CCDS7412

Canonical transcript exons

ENST00000371697 — 9 exons

Exon	Start	End
ENSE00000986568	90919131	90919268
ENSE00000986569	90918865	90918972
ENSE00000986570	90917732	90917830
ENSE00000986571	90916171	90916269
ENSE00000986572	90915782	90915880
ENSE00000986573	90915543	90915641
ENSE00001378958	90920169	90920348
ENSE00001455875	90912096	90912976
ENSE00001455887	90921001	90921087

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 99.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.8648 / max 5060.6864, expressed in 969 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110622	72.5243	922
205941	1.1869	423
205939	0.8648	349
205940	0.4958	222
205937	0.4573	169
205938	0.3356	174

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.88	gold quality
right atrium auricular region	UBERON:0006631	99.88	gold quality
cardiac atrium	UBERON:0002081	99.42	gold quality
heart left ventricle	UBERON:0002084	98.98	gold quality
cardiac ventricle	UBERON:0002082	98.58	gold quality
left ventricle myocardium	UBERON:0006566	97.53	gold quality
right lung	UBERON:0002167	97.45	gold quality
vena cava	UBERON:0004087	96.85	gold quality
heart	UBERON:0000948	96.30	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.47	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.37	gold quality
myocardium	UBERON:0002349	95.02	gold quality
gastrocnemius	UBERON:0001388	94.92	gold quality
gluteal muscle	UBERON:0002000	92.50	gold quality
muscle of leg	UBERON:0001383	92.19	gold quality
upper lobe of left lung	UBERON:0008952	89.42	gold quality
upper lobe of lung	UBERON:0008948	87.84	gold quality
heart right ventricle	UBERON:0002080	85.95	gold quality
muscle organ	UBERON:0001630	83.35	gold quality
islet of Langerhans	UBERON:0000006	80.88	gold quality
left coronary artery	UBERON:0001626	79.84	gold quality
coronary artery	UBERON:0001621	77.93	gold quality
right coronary artery	UBERON:0001625	75.67	gold quality
ascending aorta	UBERON:0001496	72.05	gold quality
thoracic aorta	UBERON:0001515	71.87	gold quality
lung	UBERON:0002048	70.95	gold quality
aorta	UBERON:0000947	70.89	gold quality
tibialis anterior	UBERON:0001385	70.53	silver quality
popliteal artery	UBERON:0002250	70.47	gold quality
tibial artery	UBERON:0007610	70.46	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	4470.57
E-MTAB-8205	yes	1589.64
E-GEOD-81383	yes	677.33
E-CURD-7	no	273.00
E-ENAD-21	no	273.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NPPA	Repression

Upstream regulators (CollecTRI, top): DDIT3, GATA4, IRF9, JUN, NFKB, NKX2-5, SMAD2, SMAD3, SMAD4, SMAD6, SSRP1, STAT2, TEAD1, TP53, ZNF804A

miRNA regulators (miRDB)

61 targeting ANKRD1, 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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5003-5P	99.61	69.13	1624

Literature-anchored findings (GeneRIF, showing 40)

• Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure. (PMID:12054667)
• CARP expression is observed by in situ hybridization in endothelial cells lining human atherosclerotic plaques, whereas lesion macrophages are devoid of CARP; it is induced by activin A in cultured intimal smooth muscle cells. (PMID:12524226)
• These findings suggest that type-specific expression patterns of ARPP and CARP are altered in skeletal muscles of amyotrophic lateral sclerosis. (PMID:12679596)
• endogenous ANKRD1 and calsequestrin are co-enriched in piglet cardiac Purkinje cells (PMID:15698842)
• CARP interacts with itself and desmin. CARP, ankrd2, and DARP contain potential coiled-coil dimerization motifs within their unique aminoterminal domains that mediate the formation of homo-dimers. (PMID:16450059)
• CARP was expressed in renal podocytes at a high level in 10 of 13 cases of crescentic glomerulonephritis, 7 of 19 cases of diabetic nephropathy, and 12 of 20 cases of lupus nephritis. (PMID:17239933)
• cloned both translocation breakpoints and mapped the ANKRD1 gene, encoding a cardiac transcriptional regulator, 130 kb proximally to the breakpoint on chromosome 10, in total anomalous pulmonary venous return, a congenital heart defect (PMID:18273862)
• Our results indicate that CARP is a sensitive and specific marker for rhabdomyosarcoma and that it will be useful for the differential diagnosis of rhabdomyosarcoma. (PMID:18656235)
• We suggest that CDH1 cytoplasmic immunolocalization as a result of increased IGF-II levels identifies those nonmuscle invasive presentations most likely to recur (PMID:18980987)
• Augmented CARP expression may be a common molecular event in failing hearts regardless of cardiomyopathic aetiology. (PMID:19359327)
• On the basis of genetic and functional analysis of CARP mutations, ANKRD1 has been identified as a new gene associated with dilated cardiomyopathy, accounting for approximately 2% of the 231 cases studied. (PMID:19525294)
• Data show that ANKRD1 is a short-lived protein whose levels are tightly regulated by the 26S proteasome. (PMID:19589340)
• ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM (PMID:19608030)
• CARP abnormalities may be involved in the pathogenesis of HCM. (PMID:19608031)
• CD45 lateral mobility is regulated by the spectrin-ankyrin cytoskeleton of T cells (PMID:20164196)
• p53 operates as an upstream effector of Ankrd1/CARP, by up regulating the proximal ANKRD1 promoter (PMID:20599664)
• CARP and its regulator calpain 3 appear to occupy a central position in the important cell fate-governing NF-kappaB pathway in skeletal muscle (PMID:20860623)
• Ankrd1 and desmin may play important roles in airway smooth muscle cell homeostasis. (PMID:22085644)
• Although analyzed in a limited number of patients, there is a considerable body of evidence that MARP proteins could be suitable candidates for prognostic and diagnostic biomarkers. (PMID:22185618)
• the 26S proteasome is the dominant regulator of Ankrd1/CARP degradation, and that Ankrd1/CARP half-life is significantly longer in cardiomyocytes (h) than endothelial cells (min). (PMID:22892129)
• Report impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue. (PMID:23572067)
• ANKRD1 has a significant role in the regulation of apoptosis in human ovarian cancer cells (PMID:24531715)
• Report structure activity relationships for ANKRD1. (PMID:25125175)
• To the Ankrd1, it is not responsive to the cardiotoxic drug Doxorubicin, suggesting that different mechanisms govern their expression in cardiac cells. (PMID:25585647)
• The association of ANKRD1 with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure. (PMID:25961010)
• These data suggest that hepatitis C virus coopts ANKRD1 for its own propagation and up-regulation of ANKRD1 may contribute to hepatitis C virus-mediated liver pathogenesis. (PMID:26860204)
• review of CARP, including its discovery, structure, and the role it plays in cardiac development and heart diseases [review] (PMID:27143260)
• ANKRD1 expression is reduced in patients with eczema herpeticum and might contribute to its pathogenesis (PMID:29371118)
• ANKRD1 overexpression associated with the epithelial-mesenchymal transition and anti-apoptosis involved in resistance to second-and third-generation epidermal growth factor receptor tyrosine kinase inhibitors. (PMID:30291293)
• To identify the p.S187F mutant of ANKRD1, which is associated with cardiac septal defects. (PMID:30659708)
• Data show that RREB1-induced upregulation of AGAP2-AS1 regulates cell proliferation and migration in PC partly through suppressing ANKRD1 and ANGPTL4 by recruiting EZH2. (PMID:30814490)
• Myocardial overexpression of ANKRD1 causes sinus venosus defects and progressive diastolic dysfunction. (PMID:31688894)
• Molecular Characterisation of Titin N2A and Its Binding of CARP Reveals a Titin/Actin Cross-linking Mechanism. (PMID:33647290)
• Muscle ankyrin repeat protein 1 (MARP1) locks titin to the sarcomeric thin filament and is a passive force regulator. (PMID:34152365)
• LncRNA RGMB-AS1 up-regulates ANKRD1 Through Competitively Sponging miR-3614-5p to Promote OSA Cell Proliferation and Invasion. (PMID:34583851)
• ANKRD1 and SPP1 as diagnostic markers and correlated with immune infiltration in biliary atresia. (PMID:34918678)
• Ferroptosis in calcium oxalate kidney stone formation and the possible regulatory mechanism of ANKRD1. (PMID:36907445)
• ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation. (PMID:38310103)
• Molecular characterization of ANKRD1 in rhabdomyosarcoma cell lines: expression, localization, and proteasomal degradation. (PMID:38396247)
• Pan-cancer integrated analysis of ANKRD1 expression, prognostic value, and potential implications in cancer. (PMID:38438492)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankrd1a	ENSDARG00000075263
danio_rerio	ankrd1b	ENSDARG00000076192
mus_musculus	Ankrd1	ENSMUSG00000024803
rattus_norvegicus	Ankrd1	ENSRNOG00000018598

Paralogs (1): ANKRD2 (ENSG00000165887)

Protein

Protein identifiers

Ankyrin repeat domain-containing protein 1 — Q15327 (reviewed: Q15327)

Alternative names: Cardiac ankyrin repeat protein, Cytokine-inducible gene C-193 protein, Cytokine-inducible nuclear protein

All UniProt accessions (2): Q15327, A0A384NYH5

UniProt curated annotations — full annotation on UniProt →

Function. May play an important role in endothelial cell activation. May act as a nuclear transcription factor that negatively regulates the expression of cardiac genes. Induction seems to be correlated with apoptotic cell death in hepatoma cells.

Subunit / interactions. Interacts with YBX1. Interacts with TTN/titin.

Subcellular location. Nucleus.

Tissue specificity. Mainly expressed in activated vascular endothelial cells. To a lower extent, also expressed in hepatoma cells.

Induction. By TNF, IL1A/interleukin-1 alpha and parthenolide.

RefSeq proteins (1): NP_055206* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF12796

UniProt features (9 total): repeat 5, chain 1, coiled-coil region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15327-F1	82.64	0.54

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-1430728	Metabolism
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 314 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_MUSCLE_TISSUE_DEVELOPMENT, MYOGENIN_Q6, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, AREB6_01, GOBP_NEUROGENESIS, KONG_E2F1_TARGETS, GOBP_SARCOMERE_ORGANIZATION

GO Biological Process (20): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of neuron projection development (GO:0010976), skeletal muscle cell differentiation (GO:0035914), response to muscle stretch (GO:0035994), positive regulation of apoptotic process (GO:0043065), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), sarcomere organization (GO:0045214), positive regulation of protein secretion (GO:0050714), cardiac muscle tissue morphogenesis (GO:0055008), cellular response to lipopolysaccharide (GO:0071222), cellular response to mechanical stimulus (GO:0071260), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to hypoxia (GO:0071456), cellular response to xenobiotic stimulus (GO:0071466), cellular response to transforming growth factor beta stimulus (GO:0071560), phospholipase C/protein kinase C signal transduction (GO:0141212), negative regulation of DNA biosynthetic process (GO:2000279), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (10): p53 binding (GO:0002039), DNA binding (GO:0003677), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), titin binding (GO:0031432), histone deacetylase binding (GO:0042826), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), R-SMAD binding (GO:0070412), transcription coregulator activity (GO:0003712), protein binding (GO:0005515)

GO Cellular Component (9): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), I band (GO:0031674), myofibril (GO:0030016), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
regulation of DNA-templated transcription	2
response to mechanical stimulus	2
cellular response to cytokine stimulus	2
transcription coregulator activity	2
regulation of transcription by RNA polymerase II	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
skeletal muscle tissue development	1
cell differentiation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
DNA damage response, signal transduction by p53 class mediator	1
regulation of DNA damage response, signal transduction by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1
myofibril assembly	1
actomyosin structure organization	1
protein secretion	1
regulation of protein secretion	1
positive regulation of protein transport	1
positive regulation of secretion by cell	1
heart morphogenesis	1
cardiac muscle tissue development	1
muscle tissue morphogenesis	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
response to interleukin-1	1
response to tumor necrosis factor	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
response to xenobiotic stimulus	1

Protein interactions and networks

STRING

2362 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKRD1	TTN	Q8WZ42	982
ANKRD1	MYPN	Q86TC9	964
ANKRD1	YBX1	P16990	753
ANKRD1	CCN1	O00622	750
ANKRD1	CCN2	P29279	733
ANKRD1	YAP1	P46937	696
ANKRD1	NEBL	O76041	686
ANKRD1	FHL2	Q14192	659
ANKRD1	CSRP3	P50461	623
ANKRD1	AMOTL2	Q9Y2J4	605
ANKRD1	LATS1	O95835	596
ANKRD1	TCAP	O15273	595
ANKRD1	ACTA2	P03996	586
ANKRD1	NEB	P20929	581
ANKRD1	CAPN3	P20807	555

IntAct

39 interactions, top by confidence:

A	B	Type	Score
CDCA7L	ANKRD1	psi-mi:“MI:0915”(physical association)	0.560
ANKRD1	NAGK	psi-mi:“MI:0915”(physical association)	0.560
ANKRD1	ZNF446	psi-mi:“MI:0915”(physical association)	0.560
ANKRD1	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
ANKRD1	MAPRE3	psi-mi:“MI:0915”(physical association)	0.560
ANKRD1	SPANXN2	psi-mi:“MI:0915”(physical association)	0.560
ANKRD1	CDCA7L	psi-mi:“MI:0915”(physical association)	0.560
PDE4DIP	ANKRD1	psi-mi:“MI:0915”(physical association)	0.440
ANKRD1	PDE4DIP	psi-mi:“MI:0403”(colocalization)	0.440
ANKRD1	NAGK	psi-mi:“MI:0915”(physical association)	0.000
ANKRD1	MEOX2	psi-mi:“MI:0915”(physical association)	0.000
ANKRD1	ZNF446	psi-mi:“MI:0915”(physical association)	0.000
ZNF446	ANKRD1	psi-mi:“MI:0915”(physical association)	0.000
MAPRE3	ANKRD1	psi-mi:“MI:0915”(physical association)	0.000
SPANXN2	ANKRD1	psi-mi:“MI:0915”(physical association)	0.000
ANKRD1	ARHGDIB	psi-mi:“MI:0915”(physical association)	0.000
DST	ANKRD1	psi-mi:“MI:0915”(physical association)	0.000
LRPPRC	ANKRD1	psi-mi:“MI:0915”(physical association)	0.000
MYBPC1	ANKRD1	psi-mi:“MI:0915”(physical association)	0.000
MYL1	ANKRD1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (40): ANKRD1 (Two-hybrid), ANKRD1 (Two-hybrid), ANKRD1 (Reconstituted Complex), ANKRD1 (Reconstituted Complex), UBE2O (Affinity Capture-MS), ANKRD1 (Two-hybrid), MYPN (Two-hybrid), ANKRD1 (Two-hybrid), ANKRD1 (Reconstituted Complex), TTN (Two-hybrid), ANKRD1 (Reconstituted Complex), ANKRD1 (Two-hybrid), ANKRD1 (Two-hybrid), ANKRD1 (Two-hybrid), ANKRD1 (Two-hybrid)

ESM2 similar proteins: A1YVX4, A2VDR2, A3AYR1, A3KMI0, A7E2S9, A9JR78, F1REV3, O70145, O73630, O77775, P19838, P19878, P25799, P41230, Q04861, Q15327, Q4V869, Q4V8X4, Q52T38, Q5RJK8, Q5U243, Q5U2S3, Q5U2X2, Q5U312, Q5XUN4, Q62240, Q63369, Q66JD7, Q6F3J0, Q6P158, Q6P5D3, Q6PGC1, Q7SIG6, Q7Z3E5, Q7Z478, Q7ZT11, Q8IWZ3, Q8VHQ3, Q95N27, Q96T49

Diamond homologs: Q15327, Q3ZBX7, Q4KL97, Q5BKI6, Q7ZT11, Q812A3, Q865U8, Q86SG2, Q8R560, Q9CR42, Q9GZV1, Q9TU71, Q9WV06

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ANKRD1	“down-regulates quantity by repression”	NPPA	“transcriptional regulation”
ZNF804A	“up-regulates quantity by expression”	ANKRD1	“transcriptional regulation”
TEAD	“up-regulates quantity by expression”	ANKRD1	“transcriptional regulation”
NKX2-5	“up-regulates quantity by expression”	ANKRD1	“transcriptional regulation”
DDIT3	“down-regulates quantity by repression”	ANKRD1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	329
Likely benign	165
Benign	23

Top pathogenic / likely-pathogenic (0)

SpliceAI

768 predictions. Top by Δscore:

Variant	Effect	Δscore
10:90915537:A:AC	donor_gain	1.0000
10:90915537:ACTT:A	donor_loss	1.0000
10:90915538:C:CC	donor_gain	1.0000
10:90915538:CT:C	donor_loss	1.0000
10:90915539:TTAC:T	donor_loss	1.0000
10:90915540:T:TG	donor_loss	1.0000
10:90915541:A:AC	donor_gain	1.0000
10:90915541:ACAC:A	donor_loss	1.0000
10:90915542:C:A	donor_loss	1.0000
10:90915542:C:CA	donor_gain	1.0000
10:90915542:CA:C	donor_gain	1.0000
10:90915542:CACA:C	donor_gain	1.0000
10:90915542:CACAG:C	donor_gain	1.0000
10:90915638:CTTC:C	acceptor_gain	1.0000
10:90915642:C:CC	acceptor_gain	1.0000
10:90915778:TCACT:T	donor_loss	1.0000
10:90915779:CAC:C	donor_loss	1.0000
10:90915780:A:AC	donor_gain	1.0000
10:90915780:ACT:A	donor_gain	1.0000
10:90915781:C:CT	donor_gain	1.0000
10:90915781:CT:C	donor_gain	1.0000
10:90915781:CTC:C	donor_gain	1.0000
10:90915781:CTCT:C	donor_gain	1.0000
10:90915781:CTCTG:C	donor_gain	1.0000
10:90915877:GCAA:G	acceptor_gain	1.0000
10:90915878:CAA:C	acceptor_gain	1.0000
10:90915878:CAAC:C	acceptor_gain	1.0000
10:90915879:AA:A	acceptor_gain	1.0000
10:90915881:C:A	acceptor_loss	1.0000
10:90915881:C:CC	acceptor_gain	1.0000

AlphaMissense

2094 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:90915819:A:G	L238P	0.999
10:90916175:T:A	D216V	0.999
10:90916175:T:G	D216A	0.999
10:90916176:C:G	D216H	0.999
10:90917736:T:A	D183V	0.999
10:90917737:C:G	D183H	0.999
10:90917801:G:C	C161W	0.999
10:90915617:C:G	A259P	0.998
10:90915786:T:A	D249V	0.998
10:90915786:T:G	D249A	0.998
10:90915787:C:G	D249H	0.998
10:90916176:C:A	D216Y	0.998
10:90916238:C:G	R195P	0.998
10:90917736:T:G	D183A	0.998
10:90917802:C:T	C161Y	0.998
10:90917803:A:G	C161R	0.998
10:90917823:C:G	R154P	0.998
10:90915601:C:G	R264P	0.997
10:90915616:G:T	A259E	0.997
10:90915855:G:T	A226E	0.997
10:90917737:C:A	D183Y	0.997
10:90917769:A:G	L172S	0.997
10:90917805:G:T	A160E	0.997
10:90917817:G:T	A156D	0.997
10:90918869:T:A	D150V	0.997
10:90915546:G:C	N282K	0.996
10:90915546:G:T	N282K	0.996
10:90915785:G:C	D249E	0.996
10:90915785:G:T	D249E	0.996
10:90915848:C:A	R228S	0.996

dbSNP variants (sampled 300 via entrez): RS1000213125 (10:90920077 T>C,G), RS1000364231 (10:90913486 C>A), RS1000824520 (10:90913833 G>T), RS1000866410 (10:90919575 T>C,G), RS1001834077 (10:90921262 C>A,T), RS1002093967 (10:90915056 T>C), RS1002283626 (10:90913591 C>G), RS1002415720 (10:90919970 T>G), RS1002444681 (10:90914778 T>G), RS1002646283 (10:90917692 A>G), RS1002700480 (10:90918033 A>G), RS1002757724 (10:90921274 T>C,G), RS1003027239 (10:90915070 A>T), RS1003651682 (10:90916290 C>T), RS1003705572 (10:90916578 G>A)

Disease associations

OMIM: gene MIM:609599 | disease phenotypes: MIM:106700, MIM:115195, MIM:192600, MIM:115200, MIM:601144, MIM:604169

GenCC curated gene-disease

Disease	Classification	Inheritance
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
congenital heart disease	Limited	Autosomal dominant
familial dilated cardiomyopathy	Limited	Autosomal dominant
familial hypertrophic cardiomyopathy	Limited	Autosomal dominant
hypertrophic cardiomyopathy	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dilated cardiomyopathy	Limited	AD
hypertrophic cardiomyopathy	Disputed	AD
congenital heart disease	Limited	AD

Mondo (15): cardiomyopathy (MONDO:0004994), congenital total pulmonary venous return anomaly (MONDO:0007130), dilated cardiomyopathy (MONDO:0005021), hypertrophic cardiomyopathy 2 (MONDO:0007266), familial hypertrophic cardiomyopathy (MONDO:0024573), hypertrophic cardiomyopathy (MONDO:0005045), dilated cardiomyopathy 1A (MONDO:0007269), Brugada syndrome (MONDO:0015263), long QT syndrome (MONDO:0002442), systolic heart failure (MONDO:0006993), left ventricular noncompaction (MONDO:0018901), hypertrophic cardiomyopathy 1 (MONDO:0008647), congenital heart disease (MONDO:0005453), (MONDO:0015470), familial dilated cardiomyopathy (MONDO:0016333)

Orphanet (9): Rare cardiomyopathy (Orphanet:167848), Congenital total pulmonary venous return anomaly (Orphanet:99125), Dilated cardiomyopathy (Orphanet:217604), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Rare hypertrophic cardiomyopathy (Orphanet:217569), Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet:300751), Brugada syndrome (Orphanet:130), Left ventricular noncompaction (Orphanet:54260), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

13 total (14 of 13 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001727	Thromboembolic stroke
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0011675	Arrhythmia
HP:0012378	Fatigue
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0100578	Lipoatrophy
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005580_148	Intraocular pressure	2.000000e-08
GCST010002_296	Refractive error	2.000000e-08
GCST010796_5263	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_5264	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_5265	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D054143	Heart Failure, Systolic	C14.280.434.676
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C566171	Cardiomyopathy, Familial Hypertrophic, 2 (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	10
Benzo(a)pyrene	decreases expression, increases expression	6
trichostatin A	affects cotreatment, increases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Particulate Matter	decreases reaction, increases abundance, decreases expression	4
cadmium sulfate	increases expression	3
Air Pollutants	increases expression, decreases expression, increases abundance	3
Estradiol	affects expression, affects cotreatment, increases expression, decreases expression	3
Aflatoxin B1	affects expression, increases expression, increases methylation	3
Cadmium Chloride	decreases expression, increases expression	3
bisphenol A	decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction, affects cotreatment, increases expression	2
Temozolomide	affects response to substance, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Ethanol	decreases expression	2
Vehicle Emissions	decreases expression, decreases reaction, increases abundance	2
Cadmium	increases expression	2
Lipopolysaccharides	decreases expression, increases expression, decreases reaction, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, affects cotreatment, increases expression	2
Cyclosporine	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
gingerenone A	increases expression	1
TAK-243	increases sumoylation	1
Esketamine	decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1

Clinical trials (associated diseases)

593 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
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart