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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
ORC4
origin recognition complex subunit 4
Chromosome 2 Β· 2q23.1
NCBI Gene: 5000Ensembl: ENSG00000115947.15HGNC: HGNC:8490UniProt: A8K7H4
95PubMed Papers
21Diseases
0Drugs
23Pathogenic Variants
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
nucleusnucleoplasmnucleolusorigin recognition complexEar-patella-short stature syndromeMeier-Gorlin syndromemicrocephalic primordial dwarfismatrial fibrillation
✦AI Summary

ORC4 is a core subunit of the origin recognition complex (ORC), a six-protein assembly essential for initiating eukaryotic DNA replication 1. ORC4 functions as an ATP-dependent DNA-binding protein that recognizes replication origins and helps establish the pre-replication complex required for DNA synthesis initiation 2. The protein contains a conserved 19-amino acid insertion helix critical for determining ORC's selectivity for replication origins; human ORC4 lacks this motif present in yeast, resulting in chr2-landscape-dependent origin recognition rather than sequence-specific binding 3. ORC4 exhibits unexpected cellular localizations beyond chr2, including formation of a cage around chr2 destined for polar body extrusion during early mammalian development, suggesting roles in mitosis and chr2 segregation beyond canonical replication functions 1. ORC4 can stimulate formation of alternative DNA structures like T.A.T triplexes in an ATP-dependent manner, potentially facilitating origin accessibility 4. Germline mutations in ORC4 cause Meier-Gorlin syndrome (MGS), a rare autosomal recessive primordial dwarfism characterized by severe growth retardation, microtia, and patellar anomalies 2. ORC1 and ORC4 mutations produce the most severe phenotypes including microcephaly 5. ORC4 dysfunction disrupts fundamental replication mechanisms, with transcriptomic evidence showing altered ORC4 expression associates with embryonic developmental arrest and compromised competence in human preimplantation embryos 6. These findings establish ORC4 as critical for both normal organismal growth and genomic stability.

Sources cited
1
ORC4 localizes to chromatin, cytoplasm, and forms structures around chromosomes; ORC proteins mark DNA replication origins and have roles in mitosis
PMID: 26453397
2
ORC4 contains a 19-amino acid insertion helix determining origin selectivity; human ORC4 lacks this motif and uses chromatin landscape for origin recognition
PMID: 33397927
3
ORC4 mutations cause Meier-Gorlin syndrome; ORC4 is a conserved eukaryotic origin recognition complex component
PMID: 21358631
4
ORC4 mutations in MGS patients associated with severe short stature and microcephaly; ORC4 mutations detected in 67-78% of MGS cases
PMID: 26381604
5
Human ORC4 stimulates formation of alternative DNA structures like triplexes in ATP-dependent manner
PMID: 18652488
6
ORC4 expression alterations associated with developmental arrest and reduced competence in human 8-cell embryos
PMID: 36943184
7
ORC4 encodes a protein involved in genome replication; mutations cause primordial dwarfism with extreme growth failure
PMID: 21979914
Disease Associationsβ“˜21
Ear-patella-short stature syndromeOpen Targets
0.77Strong
Meier-Gorlin syndromeOpen Targets
0.37Weak
microcephalic primordial dwarfismOpen Targets
0.37Weak
atrial fibrillationOpen Targets
0.32Weak
goutOpen Targets
0.26Weak
hypertension, pregnancy-inducedOpen Targets
0.24Weak
genetic disorderOpen Targets
0.19Weak
coronary artery diseaseOpen Targets
0.14Weak
major depressive disorderOpen Targets
0.13Weak
joint diseaseOpen Targets
0.11Weak
neurotic disorderOpen Targets
0.11Weak
AnxietyOpen Targets
0.10Suggestive
alcohol drinkingOpen Targets
0.09Suggestive
bone remodeling diseaseOpen Targets
0.07Suggestive
brain aneurysmOpen Targets
0.07Suggestive
Back painOpen Targets
0.04Suggestive
risk-taking behaviourOpen Targets
0.04Suggestive
mathematical abilityOpen Targets
0.03Suggestive
benign prostatic hyperplasiaOpen Targets
0.03Suggestive
type 2 diabetes mellitusOpen Targets
0.02Suggestive
Meier-Gorlin syndrome 2UniProt
Pathogenic Variants23
NM_181741.4(ORC4):c.521A>G (p.Tyr174Cys)Pathogenic
Meier-Gorlin syndrome 2|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 174
NM_181741.4(ORC4):c.36del (p.His13fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 13
NM_181741.4(ORC4):c.779del (p.Arg260fs)Likely pathogenic
Meier-Gorlin syndrome 2
β˜…β˜†β˜†β˜†2025β†’ Residue 260
NM_181741.4(ORC4):c.927dup (p.Ser310Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 310
NM_181741.4(ORC4):c.301+1G>ALikely pathogenic
not provided
β˜…β˜†β˜†β˜†2025
NM_181741.4(ORC4):c.914dup (p.Ser306fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 306
NM_181741.4(ORC4):c.520dup (p.Tyr174fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 174
NM_181741.4(ORC4):c.310C>T (p.Gln104Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 104
NM_181741.4(ORC4):c.612_613del (p.Arg205fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 205
NM_181741.4(ORC4):c.437-2A>GLikely pathogenic
not provided
β˜…β˜†β˜†β˜†2023
NM_181741.4(ORC4):c.41_42del (p.Thr14fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 14
NM_181741.4(ORC4):c.92dup (p.Ser32fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 32
NM_181741.4(ORC4):c.919C>T (p.Gln307Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 307
NM_181741.4(ORC4):c.284dup (p.Leu95fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 95
NM_181741.4(ORC4):c.332del (p.Leu111fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 111
NM_181741.4(ORC4):c.767_770del (p.Leu256fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 256
NM_181741.4(ORC4):c.956A>G (p.His319Arg)Likely pathogenic
Meier-Gorlin syndrome 2
β˜…β˜†β˜†β˜†2021β†’ Residue 319
NM_181741.4(ORC4):c.623C>G (p.Ser208Ter)Pathogenic
Meier-Gorlin syndrome 2
β˜…β˜†β˜†β˜†2021β†’ Residue 208
NM_181741.4(ORC4):c.870_873dup (p.Ala292fs)Pathogenic
Meier-Gorlin syndrome 2|not provided
β˜…β˜†β˜†β˜†2021β†’ Residue 292
NM_181741.4(ORC4):c.410C>G (p.Ser137Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2018β†’ Residue 137
View on ClinVar β†—
Related Genes
CDC6Protein interaction100%MAKProtein interaction100%MCM2Protein interaction100%MCM3Protein interaction100%MCM4Protein interaction100%MCM7Protein interaction100%
Tissue Expression6 tissues
Brain
100%
Bone Marrow
79%
Ovary
71%
Heart
65%
Liver
56%
Lung
43%
Gene Interaction Network
Click a node to explore
ORC4CDC6MAKMCM2MCM3MCM4MCM7
PROTEIN STRUCTURE
Preparing viewer…
PDB7JPO Β· 3.20 Γ… Β· EM
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.53LoF Tolerant
pLIβ“˜
0.01Tolerant
Observed/Expected LoF0.83 [0.47–1.53]
RankingsWhere ORC4 stands among ~20K protein-coding genes
  • #5,048of 20,598
    Most Researched95 Β· top quartile
  • #2,053of 5,498
    Most Pathogenic Variants23
  • #15,360of 17,882
    Most Constrained (LOEUF)1.53
Genes detectedORC4
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Meier-Gorlin syndrome.
PMID: 26381604
Orphanet J Rare Dis Β· 2015
1.00
2
ORC proteins in the mammalian zygote.
PMID: 26453397
Cell Tissue Res Β· 2016
0.90
3
Humanizing the yeast origin recognition complex.
PMID: 33397927
Nat Commun Β· 2021
0.80
4
Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome.
PMID: 21358631
Nat Genet Β· 2011
0.70
5
Protein phosphatase 1 dephosphorylates Orc2.
PMID: 24732362
Biochem Biophys Res Commun Β· 2014
0.60