ORC4

Summary

ORC4 (origin recognition complex subunit 4, HGNC:8490) is a protein-coding gene on chromosome 2q23.1, encoding Origin recognition complex subunit 4 (O43929). Component of the origin recognition complex (ORC) that binds origins of replication. It is a selective cancer dependency (DepMap: 44.7% of cell lines).

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.

Source: NCBI Gene 5000 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 239 total — 19 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 65
• Cancer dependency (DepMap): dependent in 44.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_181741

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8490
Approved symbol	ORC4
Name	origin recognition complex subunit 4
Location	2q23.1
Locus type	gene with protein product
Status	Approved
Aliases	HsORC4, Orc4p
Ensembl gene	ENSG00000115947
Ensembl biotype	protein_coding
OMIM	603056
Entrez	5000

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 29 protein_coding, 4 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000264169, ENST00000392857, ENST00000416719, ENST00000440042, ENST00000457954, ENST00000461711, ENST00000478904, ENST00000481488, ENST00000483608, ENST00000488761, ENST00000490200, ENST00000495601, ENST00000496670, ENST00000535373, ENST00000536575, ENST00000540442, ENST00000877929, ENST00000877930, ENST00000877931, ENST00000877932, ENST00000877933, ENST00000877934, ENST00000877935, ENST00000877936, ENST00000877937, ENST00000877938, ENST00000877939, ENST00000877940, ENST00000877941, ENST00000932799, ENST00000932800, ENST00000932801, ENST00000932802, ENST00000932803, ENST00000932804, ENST00000932805, ENST00000969862

RefSeq mRNA: 8 — MANE Select: NM_181741 NM_001190879, NM_001190881, NM_001190882, NM_001374270, NM_001374272, NM_002552, NM_181741, NM_181742

CCDS: CCDS2187, CCDS54404, CCDS54405

Canonical transcript exons

ENST00000392857 — 14 exons

Exon	Start	End
ENSE00000777579	147939140	147939248
ENSE00000777580	147943436	147943522
ENSE00000964199	147938298	147938393
ENSE00000964200	147938146	147938213
ENSE00001888522	147930396	147935698
ENSE00003507912	147958298	147958383
ENSE00003528247	147973448	147973524
ENSE00003553207	147948051	147948224
ENSE00003575727	147952373	147952524
ENSE00003597415	147958791	147958866
ENSE00003614309	147975902	147975975
ENSE00003665856	147972739	147972829
ENSE00003786635	147955347	147955395
ENSE00003901468	148020633	148020737

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.2321 / max 676.6745, expressed in 1798 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31069	22.9673	1786
31070	2.9147	1380
31071	1.1613	716
202418	0.1887	73

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.04	gold quality
oocyte	CL:0000023	94.83	gold quality
cortical plate	UBERON:0005343	93.93	gold quality
islet of Langerhans	UBERON:0000006	93.41	gold quality
ganglionic eminence	UBERON:0004023	93.38	gold quality
adrenal tissue	UBERON:0018303	93.28	gold quality
nephron tubule	UBERON:0001231	92.19	gold quality
embryo	UBERON:0000922	92.03	gold quality
bronchial epithelial cell	CL:0002328	92.02	gold quality
corpus callosum	UBERON:0002336	91.89	gold quality
endothelial cell	CL:0000115	91.85	gold quality
ventricular zone	UBERON:0003053	91.85	gold quality
right uterine tube	UBERON:0001302	91.66	gold quality
epithelium of bronchus	UBERON:0002031	91.44	gold quality
bronchus	UBERON:0002185	91.24	gold quality
upper leg skin	UBERON:0004262	90.70	gold quality
metanephros cortex	UBERON:0010533	90.39	gold quality
heart right ventricle	UBERON:0002080	90.12	gold quality
rectum	UBERON:0001052	90.10	gold quality
left ovary	UBERON:0002119	90.02	gold quality
secondary oocyte	CL:0000655	89.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.85	gold quality
monocyte	CL:0000576	89.81	gold quality
cortex of kidney	UBERON:0001225	89.68	gold quality
kidney epithelium	UBERON:0004819	89.66	gold quality
mononuclear cell	CL:0000842	89.65	gold quality
metanephros	UBERON:0000081	89.65	gold quality
ovary	UBERON:0000992	89.60	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.42	gold quality
leukocyte	CL:0000738	89.41	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	2817.17
E-GEOD-134144	yes	2447.77
E-HCAD-56	yes	2230.92
E-MTAB-8142	yes	93.90
E-CURD-88	yes	41.82
E-HCAD-4	yes	18.04
E-ANND-3	yes	7.71
E-CURD-135	no	3943.69
E-CURD-79	no	2037.81
E-MTAB-7316	no	1891.51
E-HCAD-6	no	1100.36
E-GEOD-75140	no	605.94
E-MTAB-6386	no	393.32
E-CURD-46	no	37.54
E-MTAB-6701	no	9.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

164 targeting ORC4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-145-5P	99.92	71.13	1836

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 44.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Biochemical characterization of the mouse homolog (PMID:10460412)
• Study using HCT116 haplo-insufficient cells and Orc2 hypomorphic cells demonstrates that the binding of human Ku to replication origins precedes that of Orc-3, -4, and -6 subunit binding. (PMID:15910003)
• DNA binding activity of HsOrc4 depends on length and structure of DNA with triplex being the protein’s preferred binding target. (PMID:19690980)
• describe 3 patients with B-cell lymphoproliferative disorders (2 with non-Hodgkin lymphoma and 1 with nonsecretory multiple myeloma) carrying a novel A286V mutation within ORC4L gene (PMID:20010161)
• identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome (PMID:21358631)
• compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 (PMID:22333897)
• HsOrc4 could have a fundamental function in the process of initiation of replication by remodeling the structure of origin of replication using the energy of supercoiled DNA. (PMID:26124052)
• Since the site of one of the missense mutations in the human ORC4 alleles is conserved between humans and yeast, we sought to determine in what way this single amino acid change affects the process of chromosome replication, by introducing the comparable mutation into yeast (orc4Y232C). (PMID:29036220)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	orc4	ENSDARG00000101161
mus_musculus	Orc4	ENSMUSG00000026761
rattus_norvegicus	Orc4	ENSRNOG00000005021
drosophila_melanogaster	Orc4	FBGN0023181

Protein

Protein identifiers

Origin recognition complex subunit 4 — O43929 (reviewed: O43929)

All UniProt accessions (4): O43929, C9J2X8, C9JGH7, Q53SE3

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 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.

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 DBF4. Interacts with POLQ.

Subcellular location. Nucleus.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ORC4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43929-1	1	yes
O43929-2	2
O43929-3	3

RefSeq proteins (8): NP_001177808, NP_001177810, NP_001177811, NP_001361199, NP_001361201, NP_002543, NP_859525, NP_859526 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR016527	ORC4	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032705	ORC4_C	Domain
IPR041664	AAA_16	Domain

Pfam: PF13191, PF14629

Enzyme classification (BRENDA):

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

UniProt features (47 total): helix 22, strand 11, turn 3, sequence variant 3, splice variant 2, mutagenesis site 2, chain 1, binding site 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
7JPO	ELECTRON MICROSCOPY	3.2
5UJ7	X-RAY DIFFRACTION	3.39
7JPQ	ELECTRON MICROSCOPY	3.5
8S0D	ELECTRON MICROSCOPY	3.6
7JPP	ELECTRON MICROSCOPY	3.7
7CTE	ELECTRON MICROSCOPY	3.8
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-O43929-F1	86.12	0.47

Functional residue map

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

Ligand- & substrate-binding residues (1): 67–74

Post-translational modifications (1): 7

Mutagenesis-validated functional residues (2):

Position	Phenotype
73	impairs orc complex formation.
159–160	impairs orc complex formation.

Function

Pathways and Gene Ontology

Reactome pathways

7 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

MSigDB gene sets: 376 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, REACTOME_DNA_REPLICATION, TGCGCANK_UNKNOWN, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, FOXO4_01, SHEPARD_BMYB_MORPHOLINO_DN, EVI1_05, MORF_ZNF10, GOBP_ORGANELLE_FISSION, GOBP_CYTOKINESIS, HFH8_01, FOXJ2_01, HFH3_01, TGACATY_UNKNOWN

GO Biological Process (4): DNA replication initiation (GO:0006270), polar body extrusion after meiotic divisions (GO:0040038), protein polymerization (GO:0051258), DNA replication (GO:0006260)

GO Molecular Function (6): nucleotide binding (GO:0000166), DNA replication origin binding (GO:0003688), ATP binding (GO:0005524), DNA binding (GO:0003677), protein binding (GO:0005515), ATP hydrolysis activity (GO:0016887)

GO Cellular Component (8): chromosome, telomeric region (GO:0000781), origin recognition complex (GO:0000808), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear origin of replication recognition complex (GO:0005664), nucleolus (GO:0005730), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA metabolic process	2
nuclear lumen	2
DNA-templated DNA replication	1
female meiotic nuclear division	1
meiotic cytokinesis	1
protein-containing complex assembly	1
DNA biosynthetic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
sequence-specific double-stranded DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleic acid binding	1
binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
chromosomal region	1
chromosome	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear chromosome	1
origin recognition complex	1
nuclear protein-containing complex	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORC4	ORC5	O43913	999
ORC4	ORC6	Q9Y5N6	998
ORC4	ORC3	Q9UBD5	996
ORC4	ORC2	Q13416	960
ORC4	ORC1	Q13415	947
ORC4	CDT1	Q9H211	930
ORC4	CDC6	Q99741	922
ORC4	CDC45	O75419	847
ORC4	MCM5	P33992	831
ORC4	MCM4	P33991	822
ORC4	MCM7	P33993	804
ORC4	MCM3	P25205	803
ORC4	MCM6	Q14566	795
ORC4	GMNN	O75496	767
ORC4	LRWD1	Q9UFC0	685

IntAct

139 interactions, top by confidence:

A	B	Type	Score
ORC1	ORC5	psi-mi:“MI:0915”(physical association)	0.870
ORC1	ORC5	psi-mi:“MI:0914”(association)	0.870
ORC2	ORC5	psi-mi:“MI:0914”(association)	0.810
ORC2	ORC5	psi-mi:“MI:0915”(physical association)	0.810
ORC2	ORC4	psi-mi:“MI:0915”(physical association)	0.810
ORC2	ORC4	psi-mi:“MI:0407”(direct interaction)	0.810
ORC2	ORC4	psi-mi:“MI:0914”(association)	0.810
ORC4	ORC2	psi-mi:“MI:0914”(association)	0.810
SGTB	SGTA	psi-mi:“MI:0914”(association)	0.670
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
ORC4	ORC6	psi-mi:“MI:0407”(direct interaction)	0.610
ORC6	ORC4	psi-mi:“MI:0407”(direct interaction)	0.610
ORC4	RRM2B	psi-mi:“MI:0915”(physical association)	0.600
RRM2B	ORC4	psi-mi:“MI:0915”(physical association)	0.600
ORC4	LACC1	psi-mi:“MI:0915”(physical association)	0.590
ORC5	ORC4	psi-mi:“MI:0407”(direct interaction)	0.590

BioGRID (175): TCF4 (Two-hybrid), RRM2B (Two-hybrid), ORC4 (Protein-peptide), ORC4 (Protein-peptide), ORC4 (Affinity Capture-MS), LACC1 (Affinity Capture-MS), ORC4 (Co-fractionation), ORC4 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), ORC4 (Affinity Capture-MS), ORC4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1J6KGJ9, A0A314KSQ4, A2RU49, A4IF87, A5PJU6, B4G0F3, B8BKI7, B9SQI7, C6JS30, E0CSI1, E0CTF3, G1SPE9, O08848, O15228, O22190, O23732, O43929, O82333, O88708, P11172, P31531, P37821, P42700, P46416, Q05B63, Q10D00, Q28DB5, Q2R483, Q2YDI2, Q3T067, Q3U1V6, Q4U3P8, Q5R514, Q5R6Z7, Q5R962, Q6GM82, Q6I581, Q6YJI5, Q7TNK6, Q7Z4G4

Diamond homologs: O43929, O88708, O93479, Q2YDI2, Q4U3P8, Q5R6Z7, Q6EWX1, Q6P9Z8, Q9SU24, Q9Y794, P54791, Q5N8Q4, A1YVX4, A2A8L1, A2AUY4, A2BIL7, A6H619, A7E320, A8DZJ1, A9LMC0, B6CHA3, D3ZD32, F4I240, F4KBP5, F6UA42, G5EBZ4, O15164, O16102, O16810, O43918, O74270, O88379, O97159, P29375, P41229, P41230, P47156, P54784, P54788, P54789

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ORC4	“form complex”	ORC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 133 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	8	30.7×	8e-08
Activation of ATR in response to replication stress	8	28.3×	8e-08
Orc1 removal from chromatin	8	16.8×	2e-06
Assembly of the pre-replicative complex	9	14.8×	1e-06
Assembly of the ORC complex at the origin of replication	7	13.6×	6e-05
Mitotic G1 phase and G1/S transition	5	10.8×	6e-03
Golgi-to-ER retrograde transport	6	9.4×	3e-03
Intra-Golgi and retrograde Golgi-to-ER traffic	6	7.4×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
DNA replication initiation	9	49.7×	7e-11

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	4
Uncertain significance	105
Likely benign	69
Benign	21

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1026709	NM_181741.4(ORC4):c.332del (p.Leu111fs)	Pathogenic
1299638	NM_181741.4(ORC4):c.623C>G (p.Ser208Ter)	Pathogenic
1338361	NM_181741.4(ORC4):c.410C>G (p.Ser137Ter)	Pathogenic
1924188	NM_181741.4(ORC4):c.284dup (p.Leu95fs)	Pathogenic
1969297	NM_181741.4(ORC4):c.310C>T (p.Gln104Ter)	Pathogenic
2050432	NM_181741.4(ORC4):c.520dup (p.Tyr174fs)	Pathogenic
211805	NM_181741.4(ORC4):c.1226del (p.Thr409fs)	Pathogenic
2178452	NM_181741.4(ORC4):c.612_613del (p.Arg205fs)	Pathogenic
2193180	NM_181741.4(ORC4):c.767_770del (p.Leu256fs)	Pathogenic
225427	NM_181741.4(ORC4):c.1A>G (p.Met1Val)	Pathogenic
2821989	NM_181741.4(ORC4):c.919C>T (p.Gln307Ter)	Pathogenic
2828556	NM_181741.4(ORC4):c.92dup (p.Ser32fs)	Pathogenic
2854351	NM_181741.4(ORC4):c.41_42del (p.Thr14fs)	Pathogenic
30296	NM_181741.4(ORC4):c.870_873dup (p.Ala292fs)	Pathogenic
3247509	NC_000002.11:g.(?148709922)(148710113_?)del	Pathogenic
3625680	NM_181741.4(ORC4):c.914dup (p.Ser306fs)	Pathogenic
4075860	GRCh37/hg19 2q22.3-23.1(chr2:148698835-148778440)x1	Pathogenic
4717758	NM_181741.4(ORC4):c.927dup (p.Ser310Ter)	Pathogenic
4729976	NM_181741.4(ORC4):c.36del (p.His13fs)	Pathogenic
1299639	NM_181741.4(ORC4):c.956A>G (p.His319Arg)	Likely pathogenic
2785032	NM_181741.4(ORC4):c.437-2A>G	Likely pathogenic
4279004	NM_181741.4(ORC4):c.779del (p.Arg260fs)	Likely pathogenic
4714281	NM_181741.4(ORC4):c.301+1G>A	Likely pathogenic

SpliceAI

2513 predictions. Top by Δscore:

Variant	Effect	Δscore
2:147938212:CT:C	acceptor_gain	1.0000
2:147938330:T:TA	donor_gain	1.0000
2:147939136:TCA:T	donor_loss	1.0000
2:147939137:CA:C	donor_loss	1.0000
2:147939138:A:AC	donor_gain	1.0000
2:147939138:A:AT	donor_loss	1.0000
2:147939138:AC:A	donor_gain	1.0000
2:147939139:C:CC	donor_gain	1.0000
2:147939139:CC:C	donor_gain	1.0000
2:147939139:CCAT:C	donor_gain	1.0000
2:147939244:AGCAT:A	acceptor_gain	1.0000
2:147939245:GCAT:G	acceptor_gain	1.0000
2:147939246:CAT:C	acceptor_gain	1.0000
2:147939246:CATC:C	acceptor_gain	1.0000
2:147939247:AT:A	acceptor_gain	1.0000
2:147939249:C:CC	acceptor_gain	1.0000
2:147955342:TTTA:T	donor_loss	1.0000
2:147955343:TTA:T	donor_loss	1.0000
2:147955344:TA:T	donor_loss	1.0000
2:147955345:ACCTT:A	donor_loss	1.0000
2:147955391:CTTCC:C	acceptor_gain	1.0000
2:147955394:CC:C	acceptor_gain	1.0000
2:147955394:CCCT:C	acceptor_loss	1.0000
2:147955395:CC:C	acceptor_gain	1.0000
2:147955395:CCTG:C	acceptor_loss	1.0000
2:147955396:C:CC	acceptor_gain	1.0000
2:147955396:CTGAA:C	acceptor_loss	1.0000
2:147955404:C:CT	acceptor_gain	1.0000
2:147958289:GATAC:G	donor_loss	1.0000
2:147958292:ACT:A	donor_loss	1.0000

AlphaMissense

2896 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:147935539:A:G	W428R	0.999
2:147935539:A:T	W428R	0.999
2:147935537:C:A	W428C	0.998
2:147935537:C:G	W428C	0.998
2:147935698:C:G	A375P	0.998
2:147938306:A:T	V349D	0.998
2:147938360:G:T	A331E	0.997
2:147938369:A:G	L328P	0.997
2:147948187:C:G	R209T	0.997
2:147952434:A:G	L176P	0.997
2:147938153:A:T	V372D	0.996
2:147938361:C:G	A331P	0.996
2:147948198:T:A	R205S	0.996
2:147948198:T:G	R205S	0.996
2:147948205:T:A	E203V	0.996
2:147952389:C:T	G191D	0.996
2:147935536:C:G	A429P	0.995
2:147935685:A:G	L379S	0.995
2:147938317:A:C	N345K	0.995
2:147938317:A:T	N345K	0.995
2:147938363:A:T	I330K	0.995
2:147948068:A:G	W249R	0.995
2:147948068:A:T	W249R	0.995
2:147948183:A:C	F210L	0.995
2:147948183:A:T	F210L	0.995
2:147948185:A:G	F210L	0.995
2:147948186:T:A	R209S	0.995
2:147948186:T:G	R209S	0.995
2:147938156:A:T	V371D	0.994
2:147938200:A:C	F356L	0.994

dbSNP variants (sampled 300 via entrez): RS1000008248 (2:147940738 C>T), RS1000031338 (2:147981389 G>A), RS1000085095 (2:147934702 G>A), RS1000141205 (2:148022666 G>A), RS1000226896 (2:148005263 G>A), RS1000253593 (2:148009080 A>T), RS1000267768 (2:147967116 AAC>A), RS1000285539 (2:147956638 A>G), RS1000324593 (2:147948258 T>C,G), RS1000371835 (2:148000176 T>A), RS1000400188 (2:147954018 A>G), RS1000427462 (2:147960937 T>C), RS1000436288 (2:148003679 C>T), RS1000443083 (2:147940405 G>A), RS1000458461 (2:147960581 G>T)

Disease associations

OMIM: gene MIM:603056 | disease phenotypes: MIM:613800

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 2	Definitive	Autosomal recessive
Meier-Gorlin syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Meier-Gorlin syndrome 2	Moderate	AR

Mondo (2): Meier-Gorlin syndrome 2 (MONDO:0013428), Meier-Gorlin syndrome (MONDO:0016817)

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

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000066	Labial hypoplasia
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000319	Smooth philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000413	Atresia of the external auditory canal
HP:0000430	Underdeveloped nasal alae
HP:0000772	Abnormal rib morphology
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001363	Craniosynostosis

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000635_18	Response to statin therapy	5.000000e-07
GCST001791_3	Urate levels	2.000000e-08
GCST006924_15	Loneliness (MTAG)	2.000000e-08
GCST007344_118	Estimated glomerular filtration rate	3.000000e-11
GCST007733_58	Serum uric acid levels	9.000000e-10
GCST007876_32	Estimated glomerular filtration rate	1.000000e-14
GCST008058_127	Estimated glomerular filtration rate	3.000000e-16
GCST008059_26	Estimated glomerular filtration rate	5.000000e-15
GCST008972_142	Urate levels	1.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0007865	loneliness measurement
EFO:0004761	uric acid measurement

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

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects methylation	1
Aspirin	increases expression	1
Calcitriol	increases expression	1
Gallic Acid	increases expression	1
Gold	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects splicing	1
Plant Extracts	affects cotreatment, increases expression	1
Progesterone	increases expression	1
Sulindac	decreases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression	1
Particulate Matter	decreases expression, increases abundance	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