PRKACA
protein-codingprotein kinase cAMP-activated catalytic subunit alpha, the group of Protein kinase A subunits|AGC family kinases
Gene summary
This gene encodes one of the catalytic subunits of protein kinase A, which exists as a tetrameric holoenzyme with two regulatory subunits and two catalytic subunits, in its inactive form. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. cAMP-dependent phosphorylation of proteins by protein kinase A is important to many cellular processes, including differentiation, proliferation, and apoptosis. Constitutive activation of this gene caused either by somatic mutations, or genomic duplications of regions that include this gene, have been associated with hyperplasias and adenomas of the adrenal cortex and are linked to corticotropin-independent Cushing's syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. Tissue-specific isoforms that differ at the N-terminus have been described, and these isoforms may differ in the post-translational modifications that occur at the N-terminus of some isoforms. [provided by RefSeq, Jan 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0030876
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009162
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0030876
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0014359
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0030876
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0031386
Submitter: ClinGen
*PRKACA* was first reported in relation to autosomal dominant cardioacrofacial dysplasia (MIM: 619142) in 2020 (Palencia-Campos et al., PMID: 33058759). This condition is characterized by short stature; facial anomalies (like midface hypoplasia and micrognathia); dental anomalies (such as diastema and hypodontia); nail dysplasia; cardiac features (including atrioventricular septal defect); long/narrow thorax; digit anomalies (like post axial polysyndactyly and brachydactyly); short long bones; and genu valgum. One recurrent missense variant, p.Gly137Arg, that has been reported in at least eight probands in four publications (PMIDs: 33058759, 33875766, 38357848, 39706863) and from one clinical lab (GeneDx; ClinVar SCV002818851) is included in this curation. One proband with an in-frame deletion and skeletal features such as low bone density, genu valgum, and patellar dislocation, as well as cardiac and muscular anomalies, was reported (PMID: 42157491). However, this proband was not scored due to lacking the digital, limb, and rib features seen in probands with the p.Gly137Arg variant. The mechanism of pathogenicity appears to be partial loss-of-function (PMID: 33058759). This gene-disease relationship is supported by just half a point of experimental evidence (expression-level data from Human Protein Atlas). Experimental data indicates that this protein is expressed in bone marrow. No scorable animal models were reported in the literature. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 9/2/2026 (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0030876
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dental; Endocrine; Musculoskeletal
Intervention: Cardiovascular; Endocrine
Rationale: In Primary pigmented nodular adrenocortical disease 4, awareness may allow early management of adrenal disease (eg, potentially including surgical intervention), which may be beneficial; Cardioacrofacial dysplasia 1 may include congenital cardiovascular anomalies (among other features), and awareness may allow prompt recognition and management of these issues
Comments: Mosaicism has been described in Cardioacrofacial dysplasia 1
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PRKACA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002730.4. 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 | 2 | 14 | 2 | 18 | ||
| missense | 3 | 44 | 47 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 3 | 52 | 14 | 2 | 71 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002721.1 | 10 | MANE Select | |
| Ensembl | ENSP00000309591.3 | 10 | MANE Select | |
| RefSeq | NP_001291278.1 | 10 | Standard | |
| RefSeq | NP_997401.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Prion diseases - Homo sapiens (human)
- Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
- Platelet activation - Homo sapiens (human)
- Cortisol synthesis and secretion - Homo sapiens (human)
- Relaxin signaling pathway - Homo sapiens (human)
Biological Process
- G2/M transition of mitotic cell cycle
- mesoderm formation
- neural tube closure
- regulation of heart rate
- stimulatory C-type lectin receptor signaling pathway
Molecular Function
- magnesium ion binding
- protein kinase activity
- protein serine/threonine kinase activity
- cAMP-dependent protein kinase activity
- protein serine/threonine/tyrosine kinase activity
Cellular Component
- acrosomal vesicle
- nucleus
- nucleoplasm
- cytoplasm
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000308677
- Coding exons
- 10
- Length
- 26397
- Individuals with no LoFs
- 125734
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125736
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.97 | 92 | 214 | 0.429 | 0.0000136 | 2331 |
| Missense (PolyPhen) | 26 | 86.582 | 0.30029 | 885 | ||
| Synonymous | -0.221 | 92 | 89.3 | 1.03 | 0.00000632 | 637 |
| Loss of Function | 3.71 | 2 | 19.8 | 0.101 | 9.39e-7 | 230 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose- mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B- alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha- difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). {ECO:0000269|PubMed:15642694, ECO:0000269|PubMed:15905176, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:17333334, ECO:0000269|PubMed:17565987, ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:21085490, ECO:0000269|PubMed:21423175, ECO:0000269|PubMed:21514275, ECO:0000269|PubMed:21812984}.;
- Disease
- DISEASE: Primary pigmented nodular adrenocortical disease 4 (PPNAD4) [MIM:615830]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24571724, ECO:0000269|PubMed:24700472, ECO:0000269|PubMed:24747643, ECO:0000269|PubMed:24855271}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.535
Intolerance Scores
- LoFtool
- 0.0911
- RVIS EVS
- -0.47
- RVIS percentile EVS
- 23.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |