ORC1

Summary

ORC1 (origin recognition complex subunit 1, HGNC:8487) is a protein-coding gene on chromosome 1p32.3, encoding Origin recognition complex subunit 1 (Q13415). Component of the origin recognition complex (ORC) that binds origins of replication.

The origin recognition complex (ORC) is a highly conserved six subunits 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. The protein encoded by this gene is the largest subunit of the ORC complex. While other ORC subunits are stable throughout the cell cycle, the levels of this protein vary during the cell cycle, which has been shown to be controlled by ubiquitin-mediated proteolysis after initiation of DNA replication. This protein is found to be selectively phosphorylated during mitosis. It is also reported to interact with MYST histone acetyltransferase 2 (MyST2/HBO1), a protein involved in control of transcription silencing. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4998 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 1 (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 441 total — 19 pathogenic, 12 likely-pathogenic
• MANE Select transcript: NM_004153

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8487
Approved symbol	ORC1
Name	origin recognition complex subunit 1
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	HSORC1, PARC1
Ensembl gene	ENSG00000085840
Ensembl biotype	protein_coding
OMIM	601902
Entrez	4998

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000371566, ENST00000371568, ENST00000852389, ENST00000921462, ENST00000921463, ENST00000921464, ENST00000959732

RefSeq mRNA: 3 — MANE Select: NM_004153 NM_001190818, NM_001190819, NM_004153

CCDS: CCDS566

Canonical transcript exons

ENST00000371568 — 17 exons

Exon	Start	End
ENSE00000915827	52388442	52388637
ENSE00000915828	52389217	52389321
ENSE00000915829	52393443	52393803
ENSE00000915830	52396046	52396364
ENSE00000915831	52397685	52397863
ENSE00000915832	52401362	52401489
ENSE00000957636	52375430	52375599
ENSE00000957637	52374810	52374897
ENSE00001064538	52381642	52381761
ENSE00001191483	52404246	52404423
ENSE00001455517	52372829	52373375
ENSE00001455522	52402129	52402228
ENSE00003466978	52385161	52385262
ENSE00003533164	52383420	52383569
ENSE00003594240	52384550	52384721
ENSE00003648305	52383830	52383937
ENSE00003658000	52385852	52385949

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 81.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4213 / max 163.9584, expressed in 1206 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12358	8.1429	1119
12359	2.0069	725
12360	0.2715	144

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.71	gold quality
ventricular zone	UBERON:0003053	80.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.46	gold quality
ganglionic eminence	UBERON:0004023	79.29	gold quality
embryo	UBERON:0000922	77.33	gold quality
bone marrow	UBERON:0002371	73.66	gold quality
mucosa of transverse colon	UBERON:0004991	72.70	gold quality
secondary oocyte	CL:0000655	72.52	gold quality
rectum	UBERON:0001052	71.92	gold quality
stromal cell of endometrium	CL:0002255	71.80	gold quality
bone marrow cell	CL:0002092	68.91	gold quality
endometrium epithelium	UBERON:0004811	68.39	gold quality
right testis	UBERON:0004534	68.09	gold quality
lymph node	UBERON:0000029	68.04	gold quality
left testis	UBERON:0004533	67.33	gold quality
testis	UBERON:0000473	67.06	gold quality
vermiform appendix	UBERON:0001154	67.01	gold quality
esophagus mucosa	UBERON:0002469	66.54	gold quality
lower esophagus mucosa	UBERON:0035834	64.69	gold quality
trabecular bone tissue	UBERON:0002483	64.68	silver quality
islet of Langerhans	UBERON:0000006	62.86	gold quality
caecum	UBERON:0001153	62.80	gold quality
buccal mucosa cell	CL:0002336	62.53	gold quality
spleen	UBERON:0002106	61.52	gold quality
granulocyte	CL:0000094	61.48	gold quality
cortical plate	UBERON:0005343	61.04	gold quality
transverse colon	UBERON:0001157	60.89	gold quality
smooth muscle tissue	UBERON:0001135	60.75	gold quality
small intestine Peyer’s patch	UBERON:0003454	60.40	gold quality
small intestine	UBERON:0002108	59.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

29 targeting ORC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-519A-2-5P	98.78	71.74	1401
HSA-MIR-520B-5P	98.78	71.74	1401
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-1271-3P	97.56	64.85	865
HSA-MIR-550A-3-5P	97.56	65.35	823
HSA-MIR-550A-5P	97.56	65.35	823
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-3674	97.01	68.86	1171
HSA-MIR-4486	96.96	60.61	931
HSA-MIR-339-5P	96.73	66.01	820

Literature-anchored findings (GeneRIF, showing 29)

• a component of the origin recognition complex (ORC) that functions in DNA replication (PMID:11716535)
• ORC2 physically interacts with ORC1 on non-chromatin nuclear structures (PMID:11779870)
• Data suggest that hOrc1p is targeted for destruction by an SCF-Skp2 complex during S phase. (PMID:11931757)
• ORC1 regulates the status of the ORC complex in human nuclei by tethering ORCs 2-5 to nuclear structures (PMID:12909626)
• the ORC1 cycle in human cells is highly linked with cell cycle progression, allowing the initiation of replication to be coordinated with the cell cycle and preventing origins from refiring (PMID:12909627)
• The precise nucleotide of binding for ORC1 was identified near the start sites for leading-strand DNA synthesis. (PMID:12912926)
• HP1 has a role in the recruitment but not in the stable association of Orc1p with heterochromatin (PMID:15454574)
• BAH domain in human Orc1 facilitates its ability to activate replication origins in vivo by promoting association of ORC with chromatin. (PMID:17066079)
• Interacts with TRF2 to achieve stable binding in pre-replication complex assembly at telomeres. These data suggest that ORC might be involved in telomere homeostasis in human cells. (PMID:18761675)
• data suggest that Orc1 is a regulator of centriole and centrosome reduplication as well as the initiation of DNA replication (PMID:19197067)
• Data show that Orc1 specifically binds hypo-phosphorylated Rb and that this interaction is competitive with the binding of Rb to E2F1. (PMID:21085491)
• in human cancer cells, RBX1 silencing causes the accumulation of DNA replication licensing proteins CDT1 and ORC1, leading to DNA double-strand breaks, DDR, G(2) arrest, and, eventually, aneuploidy (PMID:21115485)
• Mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. These mutations disrupt ORC1 functions including pre-replicative complex formation and origin activation. (PMID:21358633)
• As cells moved through the cell cycle, the local-ization of ORC1 shifted, suggesting changes in thelocalization of ORC-bound origin sequences. (PMID:22045277)
• A lethal phenotype was seen in four individuals with compound heterozygous ORC1 mutations (PMID:22333897)
• results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism (PMID:22398447)
• Data show that purified Epstein-Barr nuclear antigen 1 EBNA1 recruits purified Human Orc1 and Cdc6 onto replication origin oriP. (PMID:22589552)
• Orc1 harbors a PACT centrosome-targeting domain and a separate domain that differentially inhibits the protein kinase activities of Cyclin E-CDK2 and Cyclin A-CDK2 (PMID:22855792)
• ORC1 associated with transcription start sites of coding or noncoding RNAs. Transcription levels at the ORC1 sites directly correlated with replication timing. (PMID:23187890)
• ORC1 harbors a G-rich RNA/ssDNA-binding domain, which may be involved in the preferential binding to G-quadruplex-formable RNA/DNA by ORC. Structure modeling predicts the structural similarity between the G-rich RNA/ssDNA-binding domain of ORC1 and part of mammalian DNA methyltransferase 1. (PMID:24003239)
• Orc1 acts as a nucleating center for origin recognition complex assembly and then pre-replication complex assembly by binding to mitotic chromosomes, followed by gradual removal from chromatin during the G1 phase. (PMID:25784553)
• The opposing effects of ORC1 (represor) and CDC6 (gene activator) in controlling the level of Cyclin E ensures genome stability and a mechanism for linking directly DNA replication and cell division commitment. (PMID:27458800)
• The authors have discovered that human cell lines in culture proliferate with intact chromosomal origins of replication after disruption of both alleles of ORC2 or of the ATPase subunit, ORC1. (PMID:27906128)
• Authors report the crystal structure of Cyclin A-CDK2 complex bound to a peptide derived from ORC1 at 2.54 a resolution; structure revealed that the ORC1 peptide interacts with a hydrophobic groove, termed cyclin binding groove, of Cyclin A via a KXL motif. (PMID:31309634)
• Origin recognition complex subunit 1 regulates cell growth and metastasis in glioma by altering activation of ERK and JNK signaling pathway. (PMID:31866342)
• Multiple, short protein binding motifs in ORC1 and CDC6 control the initiation of DNA replication. (PMID:33761311)
• Origin recognition complex subunit 1 (ORC1) augments malignant behaviors of lung adenocarcinoma cells via targeting Wnt signaling. (PMID:36700467)
• Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer. (PMID:37772772)
• Origin recognition complex subunit 1(ORC1) is a potential biomarker and therapeutic target in cancer. (PMID:37833711)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	orc1	ENSDARG00000039217
mus_musculus	Orc1	ENSMUSG00000028587
rattus_norvegicus	Orc1	ENSRNOG00000008841
drosophila_melanogaster	Orc1	FBGN0286788
caenorhabditis_elegans		WBGENE00012650

Paralogs (1): CDC6 (ENSG00000094804)

Protein

Protein identifiers

Origin recognition complex subunit 1 — Q13415 (reviewed: Q13415)

Alternative names: Replication control protein 1

All UniProt accessions (1): Q13415

UniProt curated annotations — full annotation on UniProt →

Function. Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The 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.

Subunit / interactions. Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase. Interacts with CDC6 and KAT7/HBO1. Interacts with LRWD1 predominantly during the G1 phase and with less affinity during mitosis, when phosphorylated.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated during mitosis.

Disease relevance. Meier-Gorlin syndrome 1 (MGORS1) [MIM:224690] 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The BAH domain mediates binding to dimethylated histone H4 ‘Lys-20’ (H4K20me2), which is enriched at replication origins.

Similarity. Belongs to the ORC1 family.

RefSeq proteins (3): NP_001177747, NP_001177748, NP_004144* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001025	BAH_dom	Domain
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR015163	Cdc6_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041083	AAA_lid_10	Domain
IPR043151	BAH_sf	Homologous_superfamily
IPR050311	ORC1/CDC6	Family

Pfam: PF00004, PF01426, PF09079, PF17872

Enzyme classification (BRENDA):

• EC 3.6.4.B8 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (75 total): helix 18, sequence variant 14, modified residue 12, strand 8, binding site 7, region of interest 5, compositionally biased region 4, turn 2, chain 1, domain 1, site 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6P3W	X-RAY DIFFRACTION	2.54
7JPO	ELECTRON MICROSCOPY	3.2
5UJ7	X-RAY DIFFRACTION	3.39
8S0D	ELECTRON MICROSCOPY	3.6
7JPP	ELECTRON MICROSCOPY	3.7
8S0E	ELECTRON MICROSCOPY	3.8
7JPR	ELECTRON MICROSCOPY	4
8S0C	ELECTRON MICROSCOPY	4
8S0F	ELECTRON MICROSCOPY	4.1
7JPS	ELECTRON MICROSCOPY	4.4
7CTF	ELECTRON MICROSCOPY	4.8
7CTG	ELECTRON MICROSCOPY	5
8RWV	ELECTRON MICROSCOPY	6.68
5UJM	ELECTRON MICROSCOPY	18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13415-F1	67.80	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 94 (histone h4k20me2 binding)

Ligand- & substrate-binding residues (7): 500; 534–542; 620; 621; 621; 654; 720

Post-translational modifications (12): 199, 203, 252, 255, 273, 287, 326, 337, 340, 417, 420, 478

Mutagenesis-validated functional residues (1):

Position	Phenotype
620	abolished atpase activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-113507	E2F-enabled inhibition of pre-replication complex formation
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-68616	Assembly of the ORC complex at the origin of replication
R-HSA-68689	CDC6 association with the ORC:origin complex
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-68949	Orc1 removal from chromatin
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-69205	G1/S-Specific Transcription

MSigDB gene sets: 466 (showing top): REACTOME_DNA_REPLICATION, E2F_Q4_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, GOBP_CELL_CYCLE_PHASE_TRANSITION, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, MODULE_16, FOXO1_01, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, MUELLER_PLURINET, E2F_Q3, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE

GO Biological Process (3): DNA replication initiation (GO:0006270), mitotic DNA replication checkpoint signaling (GO:0033314), DNA replication (GO:0006260)

GO Molecular Function (8): DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA replication origin binding (GO:0003688), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (6): chromosome, telomeric region (GO:0000781), origin recognition complex (GO:0000808), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear origin of replication recognition complex (GO:0005664), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Assembly of the pre-replicative complex	2
DNA Replication Pre-Initiation	2
G1/S Transition	2
E2F mediated regulation of DNA replication	1
G2/M Checkpoints	1
Switching of origins to a post-replicative state	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
binding	2
cellular anatomical structure	2
DNA-templated DNA replication	1
DNA replication checkpoint signaling	1
mitotic cell cycle	1
mitotic DNA integrity checkpoint signaling	1
mitotic G2/M transition checkpoint	1
DNA biosynthetic process	1
nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
chromosomal region	1
chromosome	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear chromosome	1
origin recognition complex	1
nuclear protein-containing complex	1
cytoplasm	1

Protein interactions and networks

STRING

2648 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORC1	ORC6	Q9Y5N6	980
ORC1	ORC2	Q13416	972
ORC1	ORC5	O43913	968
ORC1	ORC4	O43929	947
ORC1	KAT7	O95251	886
ORC1	CDC45	O75419	741
ORC1	CDC23	Q9UJX2	715
ORC1	CDT1	Q9H211	692
ORC1	CDC6	Q99741	690
ORC1	ORC3	Q9UBD5	680
ORC1	CCNA2	P20248	626
ORC1	MCM3	P25205	589
ORC1	MCM7	P33993	580
ORC1	CCNA1	P78396	570
ORC1	MCM6	Q14566	569

IntAct

71 interactions, top by confidence:

A	B	Type	Score
ORC1	ORC2	psi-mi:“MI:0407”(direct interaction)	0.890
ORC1	ORC5	psi-mi:“MI:0915”(physical association)	0.870
ORC1	ORC5	psi-mi:“MI:0914”(association)	0.870
ORC1	ORC5	psi-mi:“MI:0407”(direct interaction)	0.870
ORC5	ORC1	psi-mi:“MI:0915”(physical association)	0.870
ORC1	ORC3	psi-mi:“MI:0407”(direct interaction)	0.820
ORC2	ORC5	psi-mi:“MI:0914”(association)	0.810
ORC1	CCNA2	psi-mi:“MI:0914”(association)	0.730
CSNK2B	RPS6KA4	psi-mi:“MI:0914”(association)	0.640
ORC1		psi-mi:“MI:0407”(direct interaction)	0.620
ORC3	ORC5	psi-mi:“MI:0914”(association)	0.590

BioGRID (160): ORC1 (Two-hybrid), ORC1 (Affinity Capture-MS), ORC1 (Affinity Capture-MS), CIRBP (Affinity Capture-MS), ORC1 (Affinity Capture-MS), ORC1 (Affinity Capture-MS), ORC1 (Affinity Capture-MS), ORC2 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), RFC3 (Affinity Capture-MS), SRP72 (Affinity Capture-MS), TCEB2 (Affinity Capture-MS), TRIM26 (Affinity Capture-MS), ZNF174 (Affinity Capture-MS)

ESM2 similar proteins: A3KFM7, A3KMI0, A4QNX6, B2KF05, B2RRD7, F4JZ68, F7BJB9, G5E8P1, M9PFN0, O16810, O80528, P55201, Q05D32, Q08BB5, Q09695, Q13415, Q1LYM3, Q24558, Q3KQB6, Q3U1T9, Q4R8E0, Q58DC8, Q5F3Z7, Q5FVG2, Q5SPR8, Q5XIK8, Q640I9, Q66KM5, Q68F67, Q6IVY4, Q6P158, Q6P3S1, Q6P5D3, Q7Z478, Q801R4, Q803U7, Q80Z32, Q8BG15, Q8BGS1, Q8CDK2

Diamond homologs: O16810, O74270, P41411, P54784, P54788, P54789, Q13415, Q54RM2, Q58DC8, Q5SMU7, Q6BSE2, Q710E8, Q80Z32, Q8I615, Q9JI69, Q9SU24, Q9Z1N2, O89033, O82387, Q5N897, Q8W032, Q99741, A0RYN2, A2SPC3, A3CRD6, A7I464, B6YUE9, B8D6H2, O27463, O29995, O57864, P29569, P29570, P81413, Q2FN79, Q2NIC5, Q4JAS8, Q4JCP8, Q5JET2, Q5UWT2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CDK1	up-regulates	ORC1	phosphorylation
ORC1	“form complex”	ORC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of the pre-replicative complex	6	67.5×	7e-08
Orc1 removal from chromatin	9	55.4×	2e-11
Activation of ATR in response to replication stress	5	51.8×	2e-06
Switching of origins to a post-replicative state	5	51.8×	2e-06
Synthesis of DNA	5	51.8×	2e-06
DNA Replication	5	41.0×	7e-06
G1/S Transition	5	40.2×	7e-06
Mitotic G1 phase and G1/S transition	6	38.1×	9e-07

GO biological processes:

GO term	Partners	Fold	FDR
DNA replication initiation	6	107.0×	7e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

441 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	12
Uncertain significance	197
Likely benign	134
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034052	NM_004153.4(ORC1):c.237del (p.Pro80fs)	Pathogenic
1069550	NM_004153.4(ORC1):c.2231del (p.Gly744fs)	Pathogenic
1075855	NM_004153.4(ORC1):c.1330C>T (p.Arg444Ter)	Pathogenic
1173052	NM_004153.4(ORC1):c.1865T>C (p.Leu622Pro)	Pathogenic
1173067	NC_000001.11:g.52369378_52373625del	Pathogenic
1173068	NM_004153.4(ORC1):c.217G>A (p.Glu73Lys)	Pathogenic
1323388	NM_004153.4(ORC1):c.403-2A>C	Pathogenic
1438201	NM_004153.4(ORC1):c.275del (p.Phe92fs)	Pathogenic
2090381	NM_004153.4(ORC1):c.2173_2176dup (p.Cys726fs)	Pathogenic
2873337	NM_004153.4(ORC1):c.2193_2194del (p.Glu731fs)	Pathogenic
2957738	NM_004153.4(ORC1):c.1810C>T (p.Gln604Ter)	Pathogenic
3007280	NM_004153.4(ORC1):c.703_704del (p.Lys235fs)	Pathogenic
30230	NM_004153.4(ORC1):c.380A>G (p.Glu127Gly)	Pathogenic
30234	NM_004153.4(ORC1):c.1999_2000delinsA (p.Val667fs)	Pathogenic
30235	NM_004153.4(ORC1):c.1482-2A>G	Pathogenic
3647736	NM_004153.4(ORC1):c.2049T>G (p.Tyr683Ter)	Pathogenic
3711923	NM_004153.4(ORC1):c.271C>T (p.Arg91Ter)	Pathogenic
4723354	NM_004153.4(ORC1):c.479G>A (p.Trp160Ter)	Pathogenic
632110	NM_004153.4(ORC1):c.2221_2224dup (p.Ser742Ter)	Pathogenic
1049641	NM_004153.4(ORC1):c.692del (p.Pro231fs)	Likely pathogenic
1517600	NM_004153.4(ORC1):c.1756-1G>A	Likely pathogenic
2002096	NM_004153.4(ORC1):c.1864-1G>C	Likely pathogenic
225082	NM_004153.4(ORC1):c.721+1G>C	Likely pathogenic
225109	NM_004153.4(ORC1):c.2392-1G>T	Likely pathogenic
2441664	NM_004153.4(ORC1):c.688dup (p.Thr230fs)	Likely pathogenic
30233	NM_004153.4(ORC1):c.2159G>A (p.Arg720Gln)	Likely pathogenic
3701221	NM_004153.4(ORC1):c.722-1G>A	Likely pathogenic
3780064	NM_004153.4(ORC1):c.1145del (p.Lys382fs)	Likely pathogenic
4056696	NM_004153.4(ORC1):c.2209del (p.Gln737fs)	Likely pathogenic
942210	NM_004153.4(ORC1):c.1384-1G>C	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

5584 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:52375596:C:G	A713P	0.997
1:52383471:G:C	N654K	0.997
1:52383471:G:T	N654K	0.997
1:52381718:A:G	L686P	0.996
1:52374824:C:G	A793P	0.995
1:52375550:C:G	R728P	0.995
1:52375571:C:G	R721P	0.995
1:52381741:G:C	F678L	0.995
1:52381741:G:T	F678L	0.995
1:52381743:A:G	F678L	0.995
1:52383831:T:A	E621V	0.995
1:52375548:C:G	A729P	0.994
1:52383460:A:G	L658P	0.994
1:52383475:G:T	A653D	0.994
1:52383518:A:G	W639R	0.994
1:52383518:A:T	W639R	0.994
1:52383831:T:G	E621A	0.994
1:52383846:A:T	V616D	0.994
1:52384689:C:T	G539E	0.994
1:52384696:C:A	G537W	0.994
1:52374863:C:G	A780P	0.993
1:52375580:T:A	D718V	0.993
1:52375580:T:G	D718A	0.993
1:52383831:T:C	E621G	0.993
1:52384687:T:G	K540Q	0.993
1:52384690:C:A	G539W	0.993
1:52384710:A:T	I532N	0.993
1:52385224:C:G	R507P	0.993
1:52374868:A:G	L778P	0.992
1:52375569:A:G	C722R	0.992

dbSNP variants (sampled 300 via entrez): RS1000000941 (1:52376370 C>G,T), RS1000049867 (1:52383260 G>A), RS1000138712 (1:52410033 G>A), RS1000273250 (1:52376878 C>G), RS1000306246 (1:52400824 T>A), RS1000403804 (1:52383634 A>C,T), RS1000470514 (1:52407023 C>CT), RS1000500335 (1:52387918 C>T), RS1000560920 (1:52382410 A>G), RS1000610979 (1:52388206 A>C,T), RS1000742463 (1:52408371 A>G), RS1000852932 (1:52402493 C>T), RS1000905323 (1:52401960 A>G), RS1001009093 (1:52382414 A>G), RS1001035576 (1:52376027 G>A,T)

Disease associations

OMIM: gene MIM:601902 | disease phenotypes: MIM:224690

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 1	Definitive	Autosomal recessive
Meier-Gorlin syndrome	Supportive	Autosomal dominant

Mondo (2): Meier-Gorlin syndrome 1 (MONDO:0009143), Meier-Gorlin syndrome (MONDO:0016817)

Orphanet (1): Ear-patella-short stature syndrome (Orphanet:2554)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538012	Meier-Gorlin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

69 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects expression, decreases expression	4
Cyclosporine	decreases expression	4
bisphenol A	affects expression, decreases expression	2
perfluorooctanoic acid	decreases expression, affects cotreatment	2
Cannabidiol	decreases expression	2
Niclosamide	decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
lasiocarpine	increases expression	1
propionaldehyde	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	decreases phosphorylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
2-palmitoylglycerol	increases expression	1
GW 4064	increases expression	1
GW 3965	decreases expression	1
abrine	decreases expression	1
incobotulinumtoxinA	decreases expression	1

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry