ROCK2
protein-codingRho associated coiled-coil containing protein kinase 2, the group of AGC family kinases|Pleckstrin homology domain containing
Gene summary
The protein encoded by this gene is a serine/threonine kinase that regulates cytokinesis, smooth muscle contraction, the formation of actin stress fibers and focal adhesions, and the activation of the c-fos serum response element. This protein, which is an isozyme of ROCK1 is a target for the small GTPase Rho. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~168.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*ROCK2* was first reported in relation to autosomal dominant congenital heart disease in 2017 (Bowling et al., PMID: 28554332). 4 variants (missense, frameshift) that have been reported in 4 probands in 3 publications (PMIDs: 28554332, 30622330, 31941532) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (frog model; and frog and mouse expression-level data) (PMIDs: 12832488, 21282601). The frog model indicates abnormal expression of left-right markers and anomalous heart looping in mutants. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/3/2024 (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ROCK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004850.5. 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 | 1 | 5 | 3 | 9 | ||
| missense | 118 | 5 | 123 | |||
| nonsense | 6 | 6 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 10 | 10 | ||||
| Total | 0 | 0 | 137 | 10 | 3 | 150 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004841.2 | 33 | MANE Select | |
| Ensembl | ENSP00000317985.6 | 33 | MANE Select | |
| RefSeq | NP_001308572.1 | 31 | Standard | |
| Ensembl | ENSP00000261535.3 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| rock2b | Danio rerio | Structure: cell Quality: increased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet activation - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
- Salmonella infection - Homo sapiens (human)
- Tight junction - Homo sapiens (human)
Biological Process
- positive regulation of protein phosphorylation
- aortic valve morphogenesis
- protein phosphorylation
- smooth muscle contraction
- G protein-coupled receptor signaling pathway
Molecular Function
- RNA binding
- protein serine/threonine kinase activity
- structural molecule activity
- protein binding
- ATP binding
Cellular Component
- nucleus
- centrosome
- cytosol
- plasma membrane
- cytoplasmic ribonucleoprotein granule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000315872
- Coding exons
- 33
- Length
- 168570
- Individuals with no LoFs
- 124870
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 124892
- p
- 0.0000881
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.38 | 369 | 694 | 0.532 | 0.0000344 | 9233 |
| Missense (PolyPhen) | 81 | 268.27 | 0.30193 | 3416 | ||
| Synonymous | 1.79 | 201 | 236 | 0.852 | 0.0000113 | 2374 |
| Loss of Function | 7.41 | 11 | 84.6 | 0.130 | 0.00000468 | 1068 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00019 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.000056 | 0.000055 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.000035 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation. {ECO:0000269|PubMed:10579722, ECO:0000269|PubMed:15699075, ECO:0000269|PubMed:16574662, ECO:0000269|PubMed:17015463, ECO:0000269|PubMed:19131646, ECO:0000269|PubMed:19997641, ECO:0000269|PubMed:21084279, ECO:0000269|PubMed:21147781}.;
Recessive Scores
- pRec
- 0.312
Intolerance Scores
- LoFtool
- 0.316
- RVIS EVS
- -1.02
- RVIS percentile EVS
- 8.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.965
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |