ORC4
protein-codingorigin recognition complex subunit 4, the group of Origin recognition complex |AAA ATPases
Gene summary
The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]
- ORC4L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~91.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013428
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013428
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013428
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013428
Submitter: ClinGen
The *ORC4* gene is located on chromosome 2 at 2q23.1 and encodes the origin recognition complex, subunit 4, which binds origins of replication and is required to assemble the pre-replication complex necessary to initiate DNA replication. *ORC4* was first reported in relation to autosomal recessive Meier-Gorlin syndrome 4 in 2011 (MIM 613800) (Guernsey et al., PMID: 21358631). Meier-Gorlin syndrome 4 is a syndromic disorder characterized by short stature, missing patellae, small ears, and microcephaly. Many individuals also have distinctive facial features, with small, low set ears, microstomia, micrognathia, full lips, and a narrow nose with a high nasal bridge. At least two missense, one intragenic deletion, one frameshift, and one nonsense variant have been reported in four probands in two publications (PMID: 21358631; Marinakis et al., 2021, PMID: 34008892). Evidence supporting this gene-disease relationship includes functional alteration of patient cells, biochemical function, and protein-protein interactions (Stiff et al., 2013, PMID: 23516378; McDaniel et al., 2020, PMID: 31818869). The mechanism of disease is currently unknown. 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 gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on February 17, 2023 (SOP Version 9). It was reevaluated on April 14, 2025. There was no new evidence. As a result of this reevaluation, the classification did not change.
Inheritance Pattern: AR
Disease ID:MONDO:0013428
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016817
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ORC4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181741.4. 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 | 1 | 26 | 1 | 28 | ||
| missense | 2 | 93 | 7 | 102 | ||
| nonsense | 4 | 1 | 5 | |||
| start loss | 1 | 1 | ||||
| frameshift | 12 | 1 | 1 | 14 | ||
| splice donor/acceptor (+/-2bp) | 2 | 6 | 8 | |||
| Total | 17 | 5 | 102 | 33 | 1 | 158 |
Highest pathogenic variant AF is 0.000019232297
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_859525.1 | 13 | MANE Select | |
| Ensembl | ENSP00000376597.5 | 13 | MANE Select | |
| RefSeq | NP_001177808.1 | 13 | Standard | |
| RefSeq | NP_001177810.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- Cell Cycle
- G1 to S cell cycle control
- DNA Replication
- cdk regulation of dna replication
Biological Process
- G1/S transition of mitotic cell cycle
- DNA replication
- DNA replication initiation
Molecular Function
- nucleotide binding
- DNA replication origin binding
- protein binding
- ATP binding
Cellular Component
- nuclear chromosome, telomeric region
- origin recognition complex
- nucleus
- nucleoplasm
- nuclear origin of replication recognition complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000392857
- Coding exons
- 13
- Length
- 91180
- Individuals with no LoFs
- 125674
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 66
- Defined
- 125740
- p
- 0.000262
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.203 | 231 | 222 | 1.04 | 0.0000110 | 2878 |
| Missense (PolyPhen) | 71 | 68.519 | 1.0362 | 883 | ||
| Synonymous | 0.997 | 65 | 76.1 | 0.855 | 0.00000365 | 767 |
| Loss of Function | 1.02 | 22 | 27.8 | 0.791 | 0.00000141 | 341 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00028 | 0.00027 | rare |
| South Asian | 0.00036 | 0.00036 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre- replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3. {ECO:0000269|PubMed:22427655}.;
- Disease
- DISEASE: Meier-Gorlin syndrome 2 (MGORS2) [MIM:613800]: A syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal. {ECO:0000269|PubMed:21358631, ECO:0000269|PubMed:21358632}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.119
Intolerance Scores
- RVIS EVS
- 0.82
- RVIS percentile EVS
- 87.95
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |