ALPK3

Summary

ALPK3 (alpha kinase 3, HGNC:17574) is a protein-coding gene on chromosome 15q25.3, encoding Alpha-protein kinase 3 (Q96L96). Involved in cardiomyocyte differentiation.

Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in cardiac muscle cell development. Predicted to be active in nucleus. Implicated in hypertrophic cardiomyopathy 27.

Source: NCBI Gene 57538 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertrophic cardiomyopathy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 3,356 total — 181 pathogenic, 75 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes
• MANE Select transcript: NM_020778

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17574
Approved symbol	ALPK3
Name	alpha kinase 3
Location	15q25.3
Locus type	gene with protein product
Status	Approved
Aliases	MAK, KIAA1330, Midori
Ensembl gene	ENSG00000136383
Ensembl biotype	protein_coding
OMIM	617608
Entrez	57538

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000258888, ENST00000558077, ENST00000934403

RefSeq mRNA: 1 — MANE Select: NM_020778 NM_020778

CCDS: CCDS10333

Canonical transcript exons

ENST00000258888 — 14 exons

Exon	Start	End
ENSE00000924573	84859243	84859390
ENSE00000924574	84859776	84859903
ENSE00000924575	84860037	84860072
ENSE00000924576	84862635	84862915
ENSE00000924577	84863552	84863640
ENSE00001184683	84856392	84858555
ENSE00001184691	84839702	84840932
ENSE00001184697	84838980	84839097
ENSE00001184701	84827484	84827605
ENSE00001184704	84823330	84823368
ENSE00001184712	84817356	84817595
ENSE00001240203	84868111	84873479
ENSE00003625360	84867317	84867365
ENSE00003629489	84864442	84864665

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 98.38.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2363 / max 103.1461, expressed in 352 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148146	0.8392	278
148148	0.1824	71
148150	0.1254	69
148147	0.0450	21
207631	0.0246	13
148149	0.0197	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	98.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.91	gold quality
gluteal muscle	UBERON:0002000	97.26	gold quality
muscle of leg	UBERON:0001383	97.17	gold quality
apex of heart	UBERON:0002098	97.15	gold quality
skeletal muscle organ	UBERON:0014892	96.04	gold quality
muscle organ	UBERON:0001630	96.03	gold quality
heart left ventricle	UBERON:0002084	95.52	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.46	gold quality
cardiac ventricle	UBERON:0002082	95.29	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.00	gold quality
tibialis anterior	UBERON:0001385	94.97	gold quality
deltoid	UBERON:0001476	94.78	gold quality
skeletal muscle tissue	UBERON:0001134	94.63	gold quality
biceps brachii	UBERON:0001507	94.63	gold quality
right atrium auricular region	UBERON:0006631	93.73	gold quality
heart	UBERON:0000948	92.86	gold quality
quadriceps femoris	UBERON:0001377	92.60	gold quality
vastus lateralis	UBERON:0001379	92.37	gold quality
cardiac atrium	UBERON:0002081	92.36	gold quality
muscle tissue	UBERON:0002385	91.47	gold quality
triceps brachii	UBERON:0001509	90.89	gold quality
ascending aorta	UBERON:0001496	90.41	gold quality
thoracic aorta	UBERON:0001515	90.23	gold quality
pituitary gland	UBERON:0000007	89.99	gold quality
adrenal tissue	UBERON:0018303	89.38	gold quality
aorta	UBERON:0000947	89.25	gold quality
descending thoracic aorta	UBERON:0002345	88.84	gold quality
islet of Langerhans	UBERON:0000006	88.71	gold quality
popliteal artery	UBERON:0002250	88.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.48

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

197 targeting ALPK3, 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-4481	100.00	66.42	1669
HSA-MIR-4673	100.00	66.64	1490
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-4262	100.00	73.26	3931
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4731-5P	99.89	67.23	2537

Literature-anchored findings (GeneRIF, showing 10)

• Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy. (PMID:26846950)
• ALPK3 variant segregated with hypertrophic cardiomyopathy in 3 affected members of the family. (PMID:28223422)
• ALPK3 should be included in the list of genes to be considered in genetic studies for patients affected with pediatric syndromic cardiomyopathy. (PMID:30046096)
• Phenotypic spectrum of ALPK3-related cardiomyopathy in a consanguineous family from Oman has been reported. (PMID:31074094)
• Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants. (PMID:32480058)
• Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants. (PMID:33076350)
• A Pathogenic Variant in ALPK3 Is Associated With an Autosomal Dominant Adult-onset Hypertrophic Cardiomyopathy. (PMID:33191771)
• Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy. (PMID:34263907)
• MicroRNA-384-5p protects against cardiac hypertrophy via the ALPK3 signaling pathway. (PMID:35510648)
• Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere. (PMID:36321451)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	alpk3a	ENSDARG00000078989
danio_rerio	alpk3b	ENSDARG00000105630
mus_musculus	Alpk3	ENSMUSG00000038763
rattus_norvegicus	Alpk3	ENSRNOG00000011659
drosophila_melanogaster	bt	FBGN0005666
caenorhabditis_elegans		WBGENE00001000
caenorhabditis_elegans		WBGENE00006759

Paralogs (9): SPEG (ENSG00000072195), MYOT (ENSG00000120729), PALLD (ENSG00000129116), MYPN (ENSG00000138347), HMCN1 (ENSG00000143341), OBSCN (ENSG00000154358), IGFN1 (ENSG00000163395), CCDC141 (ENSG00000163492), SPEGNB (ENSG00000286095)

Protein

Protein identifiers

Alpha-protein kinase 3 — Q96L96 (reviewed: Q96L96)

Alternative names: Muscle alpha-protein kinase

All UniProt accessions (1): Q96L96

UniProt curated annotations — full annotation on UniProt →

Function. Involved in cardiomyocyte differentiation.

Subcellular location. Nucleus.

Disease relevance. Cardiomyopathy, familial hypertrophic, 27 (CMH27) [MIM:618052] A form of hypertrophic cardiomyopathy, a heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. CMH27 is a severe, early-onset form with features of hypertrophic and dilated cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein kinase superfamily. Alpha-type protein kinase family. ALPK subfamily.

RefSeq proteins (1): NP_065829* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR004166	a-kinase_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF02816, PF07679

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (52 total): sequence variant 21, compositionally biased region 16, region of interest 7, domain 3, modified residue 2, chain 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96L96-F1	49.15	0.14

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 (2): 228, 1222

Disulfide bonds (1): 1296–1346

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 356 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, chr6p24, MODULE_64, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, MODULE_511, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEGATIVE_REGULATION_OF_ORGANELLE_ASSEMBLY, ATGTTAA_MIR302C, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_PHOTORECEPTOR_CELL_MAINTENANCE, GOBP_CILIUM_ORGANIZATION

GO Biological Process (4): heart development (GO:0007507), cardiac muscle cell development (GO:0055013), protein phosphorylation (GO:0006468), cardiac muscle cell differentiation (GO:0055007)

GO Molecular Function (5): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	2
animal organ development	1
circulatory system development	1
striated muscle cell development	1
cardiac cell development	1
cardiac muscle cell differentiation	1
phosphorylation	1
protein modification process	1
cardiocyte differentiation	1
cardiac muscle tissue development	1
striated muscle cell differentiation	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

856 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALPK3	EIF2AK3	Q9NZJ5	791
ALPK3	PAX4	O43316	710
ALPK3	MYBPC3	Q14896	511
ALPK3	CCDC174	Q6PII3	505
ALPK3	ALPK1	Q96QP1	480
ALPK3	ZNF592	Q92610	479
ALPK3	ATP8B2	P98198	435
ALPK3	TRPM6	Q9BX84	433
ALPK3	HSPA5	P11021	432
ALPK3	MSS51	Q4VC12	432
ALPK3	MYL3	P08590	424
ALPK3	EHD3	Q9NZN3	423
ALPK3	WDR73	Q6P4I2	419
ALPK3	MYH7	P12883	418
ALPK3	TNNT2	P45379	411

IntAct

13 interactions, top by confidence:

A	B	Type	Score
ALPK3	PSMD1	psi-mi:“MI:0915”(physical association)	0.400
ALPK3	HNRNPA1	psi-mi:“MI:0915”(physical association)	0.400
ALPK3	HMGN2	psi-mi:“MI:0915”(physical association)	0.400
ALPK3	H1-0	psi-mi:“MI:0915”(physical association)	0.400
ALPK3	RPS11	psi-mi:“MI:0915”(physical association)	0.400
ALPK3	SRPRB	psi-mi:“MI:0915”(physical association)	0.400
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AHRR	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): SRPRB (Proximity Label-MS), PSMD1 (Proximity Label-MS), ALPK3 (Proximity Label-MS), ALPK3 (Proximity Label-MS), ALPK3 (Proximity Label-MS), ALPK3 (Proximity Label-MS), ALPK3 (Proximity Label-MS), ALPK3 (Affinity Capture-MS), ALPK3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A1B0GUA9, A2TJV2, A4FU49, A6NDB9, A6X8Z5, D3ZAQ5, P0C671, P10636, P10637, P48681, P58871, Q14676, Q2YDF7, Q3MI48, Q4R729, Q5EBJ4, Q5PSV9, Q5S6V2, Q5SWP3, Q5TM66, Q5TM68, Q5U2M8, Q5YCV9, Q5YCW0, Q5YCW1, Q640N3, Q68A65, Q68DA7, Q6NYC8, Q6ZW13, Q767L8, Q7YR40, Q7Z6I6, Q811Q2, Q8BHB9, Q8BHW6, Q8BQ30, Q8CB87, Q8CC96, Q8IXJ9

Diamond homologs: A2AAJ9, A2ABU4, O88599, P12960, P14781, P28685, P52179, P54296, P68500, P70402, P97527, P97528, Q02173, Q07409, Q12860, Q13203, Q14896, Q28106, Q2EY15, Q2VWP7, Q2VWP9, Q589G5, Q5PQM4, Q5VTT5, Q62234, Q62682, Q63198, Q7ZW34, Q86TB3, Q91ZB0, Q924C5, Q96JA1, Q96L96, Q98936, Q9P232, A2AJ76, A2ASS6, A8DYP0, D3YXG0, D3ZEY0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

3356 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	181
Likely pathogenic	75
Uncertain significance	1830
Likely benign	949
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028191	NM_020778.5(ALPK3):c.913C>T (p.Gln305Ter)	Pathogenic
1064814	NM_020778.5(ALPK3):c.4154del (p.Pro1385fs)	Pathogenic
1072103	NC_000015.10:g.84816946del	Pathogenic
1187004	NM_020778.5(ALPK3):c.589G>T (p.Glu197Ter)	Pathogenic
1323072	NM_020778.5(ALPK3):c.2471delinsTCATT (p.Ser824fs)	Pathogenic
1360384	NM_020778.5(ALPK3):c.2536G>T (p.Gly846Ter)	Pathogenic
1361449	NM_020778.5(ALPK3):c.496_509del (p.Val166fs)	Pathogenic
1368779	NM_020778.5(ALPK3):c.3884G>A (p.Trp1295Ter)	Pathogenic
1376298	NM_020778.5(ALPK3):c.2437dup (p.Val813fs)	Pathogenic
1385644	NM_020778.5(ALPK3):c.4014del (p.Pro1338_Val1339insTer)	Pathogenic
1399264	NM_020778.5(ALPK3):c.3231_3232del (p.Asp1077fs)	Pathogenic
1414127	NM_020778.5(ALPK3):c.3340C>T (p.Arg1114Ter)	Pathogenic
1421182	NM_020778.5(ALPK3):c.721dup (p.Glu241fs)	Pathogenic
1435620	NM_020778.5(ALPK3):c.3890dup (p.Phe1298fs)	Pathogenic
1440728	NM_020778.5(ALPK3):c.2127del (p.Thr710fs)	Pathogenic
1451440	NM_020778.5(ALPK3):c.3404_3411dup (p.Ser1138fs)	Pathogenic
1451606	NM_020778.5(ALPK3):c.2131C>T (p.Gln711Ter)	Pathogenic
1452337	NM_020778.5(ALPK3):c.1804C>T (p.Gln602Ter)	Pathogenic
1452365	NM_020778.5(ALPK3):c.3134_3659del (p.Asp1045fs)	Pathogenic
1452833	NM_020778.5(ALPK3):c.427C>T (p.Arg143Ter)	Pathogenic
1453301	NM_020778.5(ALPK3):c.4493dup (p.Pro1499fs)	Pathogenic
1453869	NM_020778.5(ALPK3):c.3437_3438dup (p.Ala1147fs)	Pathogenic
1453872	NM_020778.5(ALPK3):c.750G>A (p.Trp250Ter)	Pathogenic
1454150	NM_020778.5(ALPK3):c.762_763del (p.Glu254fs)	Pathogenic
1454549	NM_020778.5(ALPK3):c.4564_4565insT (p.Asp1522fs)	Pathogenic
1455205	NM_020778.5(ALPK3):c.634del (p.Thr212fs)	Pathogenic
1455358	NM_020778.5(ALPK3):c.664C>T (p.Gln222Ter)	Pathogenic
1455524	NM_020778.5(ALPK3):c.1438del (p.Arg480fs)	Pathogenic
1455623	NM_020778.5(ALPK3):c.2612del (p.Pro871fs)	Pathogenic
1455715	NM_020778.5(ALPK3):c.1626del (p.Gln543fs)	Pathogenic

SpliceAI

5307 predictions. Top by Δscore:

Variant	Effect	Δscore
15:84827604:AGG:A	donor_loss	1.0000
15:84827605:GGTAA:G	donor_loss	1.0000
15:84827606:G:GA	donor_loss	1.0000
15:84827606:G:GG	donor_gain	1.0000
15:84838975:CTCA:C	acceptor_loss	1.0000
15:84838976:TCA:T	acceptor_loss	1.0000
15:84838978:A:AG	acceptor_gain	1.0000
15:84838978:AG:A	acceptor_gain	1.0000
15:84838979:G:A	acceptor_gain	1.0000
15:84838979:G:GA	acceptor_gain	1.0000
15:84838979:GGA:G	acceptor_gain	1.0000
15:84838979:GGAT:G	acceptor_gain	1.0000
15:84838979:GGATA:G	acceptor_gain	1.0000
15:84839093:TACAG:T	donor_loss	1.0000
15:84839094:ACAG:A	donor_loss	1.0000
15:84839096:AGGTG:A	donor_loss	1.0000
15:84839097:GG:G	donor_loss	1.0000
15:84839098:GT:G	donor_loss	1.0000
15:84839099:T:G	donor_loss	1.0000
15:84859387:GGAG:G	donor_gain	1.0000
15:84859388:GAGG:G	donor_gain	1.0000
15:84859902:GG:G	donor_gain	1.0000
15:84859903:GG:G	donor_gain	1.0000
15:84863548:ACAGG:A	acceptor_gain	1.0000
15:84863549:CAG:C	acceptor_loss	1.0000
15:84863550:A:AG	acceptor_gain	1.0000
15:84863550:AG:A	acceptor_gain	1.0000
15:84863550:AGG:A	acceptor_gain	1.0000
15:84863550:AGGG:A	acceptor_gain	1.0000
15:84863551:G:GT	acceptor_gain	1.0000

AlphaMissense

12240 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:84839003:T:A	W312R	0.999
15:84839003:T:C	W312R	0.999
15:84839727:T:G	Y352D	0.999
15:84827588:T:C	F298S	0.998
15:84839005:G:C	W312C	0.998
15:84839005:G:T	W312C	0.998
15:84839740:C:A	A356D	0.998
15:84827600:T:A	V302D	0.997
15:84839085:T:C	L339P	0.997
15:84859350:T:A	W1511R	0.997
15:84859350:T:C	W1511R	0.997
15:84827537:T:C	F281S	0.996
15:84827593:T:C	C300R	0.996
15:84839731:A:C	Q353P	0.996
15:84839734:C:A	A354D	0.996
15:84839747:C:A	N358K	0.996
15:84839747:C:G	N358K	0.996
15:84839779:T:C	L369P	0.996
15:84864629:T:A	W1765R	0.996
15:84864629:T:C	W1765R	0.996
15:84827536:T:C	F281L	0.995
15:84827538:T:A	F281L	0.995
15:84827538:T:G	F281L	0.995
15:84827595:C:G	C300W	0.995
15:84839004:G:C	W312S	0.995
15:84839727:T:A	Y352N	0.995
15:84839736:T:C	S355P	0.995
15:84859311:T:C	C1498R	0.995
15:84863595:T:C	F1687S	0.995
15:84839733:G:C	A354P	0.994

dbSNP variants (sampled 300 via entrez): RS1000019396 (15:84842314 G>A), RS1000055778 (15:84871149 A>C), RS1000066551 (15:84826468 G>A), RS1000094025 (15:84819117 G>A,T), RS1000115945 (15:84856591 T>C), RS1000173532 (15:84852798 C>T), RS1000191158 (15:84855840 A>C,G,T), RS1000274769 (15:84819568 G>A,T), RS1000357679 (15:84858624 C>T), RS1000437369 (15:84852796 G>A), RS1000488155 (15:84852389 G>A,C), RS1000522035 (15:84832077 T>C), RS1000681519 (15:84838777 G>A), RS1000753658 (15:84839046 C>A,G), RS1000774457 (15:84858983 C>A,G,T)

Disease associations

OMIM: gene MIM:617608 | disease phenotypes: MIM:618052, MIM:192600, MIM:192350, MIM:612124

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy, familial hypertrophic 27	Definitive	Autosomal recessive
hypertrophic cardiomyopathy	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Definitive	AR
hypertrophic cardiomyopathy	Strong	AD

Mondo (9): cardiomyopathy, familial hypertrophic 27 (MONDO:0054838), neurodevelopmental disorder (MONDO:0700092), cardiomyopathy (MONDO:0004994), familial hypertrophic cardiomyopathy (MONDO:0024573), hypertrophic cardiomyopathy (MONDO:0005045), VACTERL/vater association (MONDO:0008642), dilated cardiomyopathy (MONDO:0005021), hypertrophic cardiomyopathy 12 (MONDO:0012804), hearing loss disorder (MONDO:0005365)

Orphanet (6): Rare cardiomyopathy (Orphanet:167848), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Rare hypertrophic cardiomyopathy (Orphanet:217569), VACTERL/VATER association (Orphanet:887), Dilated cardiomyopathy (Orphanet:217604), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

23 total (24 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001059	Pterygium
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001653	Mitral regurgitation
HP:0001657	Prolonged QT interval
HP:0001667	Right ventricular hypertrophy
HP:0001695	Cardiac arrest
HP:0001706	Endocardial fibroelastosis
HP:0001790	Nonimmune hydrops fetalis
HP:0002119	Ventriculomegaly
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0005144	Ventricular septal hypertrophy
HP:0005157	Concentric hypertrophic cardiomyopathy
HP:0005180	Tricuspid regurgitation
HP:0006670	Impaired myocardial contractility
HP:0011463	Childhood onset
HP:0025168	Left ventricular diastolic dysfunction
HP:0031319	Cardiomyocyte hypertrophy
HP:0034197	Third trimester onset
HP:0034198	Second trimester onset
HP:0001644	Dilated cardiomyopathy

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001280_12	Alzheimer’s disease (age of onset)	9.000000e-06
GCST001280_6	Alzheimer’s disease (age of onset)	9.000000e-06
GCST002003_4	Adverse response to chemotherapy (neutropenia/leucopenia) (gemcitabine)	4.000000e-06
GCST004521_253	Autism spectrum disorder or schizophrenia	6.000000e-11
GCST004824_11	P wave terminal force	6.000000e-10
GCST004824_4	P wave terminal force	4.000000e-09
GCST006803_69	Schizophrenia	9.000000e-10
GCST008103_25	Bipolar disorder	3.000000e-08
GCST009391_1360	Metabolite levels	9.000000e-07
GCST010320_109	PR interval	3.000000e-16
GCST010321_47	PR interval	1.000000e-17
GCST011198_1	Left ventricular end-systolic volume	3.000000e-06
GCST011208_4	Left ventricular mass to end-diastolic volume ratio	4.000000e-12
GCST011214_5	Left ventricle wall thickness	2.000000e-10
GCST011217_9	Left ventricular global circumferential strain	4.000000e-07
GCST012099_18	Hypertrophic cardiomyopathy (sarcomere negative)	9.000000e-07
GCST90020028_1440	Hip circumference adjusted for BMI	2.000000e-12
GCST90020028_1442	Hip circumference adjusted for BMI	3.000000e-10

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0008379	P wave terminal force measurement
EFO:0010366	lysophosphatidylethanolamine 16:0 measurement
EFO:0004462	PR interval
EFO:0008206	left ventricular systolic function measurement
EFO:0010556	Left ventricular mass to end-diastolic volume ratio
EFO:0008205	left ventricular structural measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
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
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066155 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Other alpha kinase family kinases

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	5
trichostatin A	affects cotreatment, decreases expression	3
aristolochic acid I	increases expression	1
bisphenol A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
aflatoxin B2	increases methylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects 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
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
incobotulinumtoxinA	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Catechin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression	1
Estradiol	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Thiram	increases expression	1
Triclosan	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	increases expression	1
S-Nitrosoglutathione	increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5659840	Binding	Inhibition of human recombinant MAK at 15 nM in presence of ATP by radiometric assay relative to control	A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress. — iScience

Cellosaurus cell lines

5 cell lines: 5 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4ZQ	ZZUNEUi015-A	Induced pluripotent stem cell	Male
CVCL_D0LF	SCVIi096-A	Induced pluripotent stem cell	Male
CVCL_D0LG	SCVIi097-A	Induced pluripotent stem cell	Male
CVCL_D0LH	SCVIi098-A	Induced pluripotent stem cell	Male
CVCL_D0LI	SCVIi099-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

527 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
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
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