ALPK3

protein-coding

alpha kinase 3, the group of I-set domain containing

Gene summary

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. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_020778.5

Inheritance

AR, AD, SD

ClinVar variants

P:299U:1551B:913

Top phenotype

Cardiomyopathy, familial hypertrophic 27

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr15:84,817,356-84,873,479

External References & Databases

Ensembl (ENSG00000136383)

Transcript & Mutation Effects

hg38 • Region Span ~56.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiomyopathy, familial hypertrophic 27DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054838

Submitter: G2P

cardiomyopathy, familial hypertrophic 27STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054838

Submitter: Labcorp Genetics (formerly Invitae)

cardiomyopathy, familial hypertrophic 27STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054838

Submitter: Labcorp Genetics (formerly Invitae)

cardiomyopathy, familial hypertrophic 27MODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0054838

Submitter: Ambry Genetics

cardiomyopathy, familial hypertrophic 27STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054838

Submitter: G2P

hypertrophic cardiomyopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

ALPK3 encodes for protein α-kinase 3, an essential cardiac pseudokinase which functions to aid in myosin-mediated force buffering and sarcomere proteostasis. ALPK3 was first reported in relation to autosomal dominant HCM in 2018 (Jaouadi et al., 2018 PMID: 30046096). At least 38 variants (nonsense, frameshift, and splice site) have been reported in probands in five publications (PMIDs: 34263907, 32480058, 30046096, 33191771, 37973666) are included in this curation. Variants in this gene segregate in at least three families. Two case-control studies showed that the proportion of ALPK3 loss-of-function variants in cardiomyopathy cohorts was significantly higher than control cohorts. More evidence is available in the literature, however, the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is loss of function and this gene-disease relationship is supported experimental evidence included biochemical function, expression, and models (PMIDs: 11418590, 36321451, 39196058), reaching the maximum score of 6 with the inclusion of the a recent knock-in mouse model which demonstrated a hypertrophic response following chronic adrenergic challenge, and partial rescue of the cellular phenotype by Mavacamten (Leinhos L, et al., 2024 https://www.biorxiv.org/content/10.1101/2024.09.30.615779v1). In summary, ALPK3 has a strong association with autosomal dominant HCM; this has been demonstrated in both research and clinical settings. An analysis will be performed separately to determine the strength of evidence for ALPK3 in an autosomal recessive cardiomyopathy. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on December 19, 2023.

hypertrophic cardiomyopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005045

Submitter: ClinGen

*ALPK3* was first reported in relation to autosomal recessive hypertrophic cardiomyopathy in 2016 (Almomani et al., 2016; PMID:26846950). At least 22 variants (nonsense, frameshift, missense, and splice site) that have been reported in 19 probands in 8 publications (PMIDs: 26846950, 27106955, 33076350, 28630369, 30046096, 31074094, 34862804, 32480058) are included in this curation. Variants in this gene segregated in at least 4 families. More evidence is available in the literature, however the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is homozygous loss of function. This gene-disease relationship is supported by biochemical function, expression, functional alterations (in patient and non-patient cells), and an animal model (PMIDs: 27106955, 11418590, 21441111). In summary, *ALPK3* is DEFINITIVELY associated with autosomal recessive hypertrophic cardiomyopathy, and has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. An analysis to determine the strength of evidence for ALPK3 in an autosomal dominant cardiomyopathy will be performed separately. The relationship between ALPK3 and autosomal recessive hypertrophic cardiomyopathy was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy GCEP on February 2, 2017. It was re-evaluated on February 7, 2022. As a result of this recuration, the classification changed from the original Strong to Definitive. This classification was approved by the ClinGen Hereditary Cardiovascular Diseases GCEP on February 7, 2022.

cardiomyopathy, familial hypertrophic 27STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0054838

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cardiomyopathy, familial hypertrophic 27AD/AR

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Individuals may manifest with early-onset, severe cardiomyopathy, and awareness may allow medical and/or surgical management; Heterozygotes may also be at increased risk of cardiomyopathy, and awareness may be beneficial to allow surveillance and potential management

Refs: 26846950; 27106955; 28223422

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALPK3 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 2363

Cardiovascular phenotypeTotal: 1564

ALPK3-related disorderTotal: 308

not specifiedTotal: 283

Cardiomyopathy, familial hypertrophic 27Total: 179

Hypertrophic cardiomyopathyTotal: 13

CardiomyopathyTotal: 11

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020778.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			15 clinvar	709 clinvar	1 clinvar	725
missense		1 clinvar	1506 clinvar	194 clinvar	8 clinvar	1709
nonsense	59 clinvar	41 clinvar	7 clinvar	1 clinvar		108
start loss			3 clinvar			3
frameshift	98 clinvar	65 clinvar	12 clinvar			175
splice donor/acceptor (+/-2bp)		35 clinvar	8 clinvar			43
Total	157	142	1551	904	9	2763

Highest pathogenic variant AF is 0.00013235759

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020778.5	RefSeq	NP_065829.4	14	MANE Select
ENST00000258888.6	Ensembl	ENSP00000258888.6	14	MANE Select
ENST00000934403.1	Ensembl	ENSP00000604462.1	13	Standard
ENST00000934403.2	Ensembl	ENSP00000604462.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein phosphorylation
heart development
cardiac muscle cell development

Molecular Function

protein serine/threonine kinase activity
ATP binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258888
Coding exons: 14
Length: 56803
Individuals with no LoFs: 125620
Homozygous LoFs: 0
Heterozygous LoFs: 128
Defined: 125748
p: 0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.131	1061	1.07e+3	0.989	0.0000637	12084
Missense (PolyPhen)		349	360.46	0.9682		3997
Synonymous	-0.395	465	454	1.02	0.0000283	4177
Loss of Function	2.15	48	67.0	0.716	0.00000358	757

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00056	0.00055	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00055	0.00054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00068	0.00067	rare
South Asian	0.00050	0.00049	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in cardiomyocyte differentiation. {ECO:0000305|PubMed:26846950, ECO:0000305|PubMed:27106955, ECO:0000305|PubMed:28630369, ECO:0000305|PubMed:30046096}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:26846950, ECO:0000269|PubMed:27106955, ECO:0000269|PubMed:28630369, ECO:0000269|PubMed:30046096}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.805
RVIS EVS: 0.23
RVIS percentile EVS: 68.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0827

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium