ORC6

Summary

ORC6 (origin recognition complex subunit 6, HGNC:17151) is a protein-coding gene on chromosome 16q11.2, encoding Origin recognition complex subunit 6 (Q9Y5N6). Component of the origin recognition complex (ORC) that binds origins of replication. It is a common-essential gene (DepMap: required in 99.4% of cancer 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. The protein encoded by this gene is a subunit of the ORC complex. Gene silencing studies with small interfering RNA demonstrated that this protein plays an essential role in coordinating chromosome replication and segregation with cytokinesis.

Source: NCBI Gene 23594 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 3 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 183 total — 12 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 79
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_014321

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17151
Approved symbol	ORC6
Name	origin recognition complex subunit 6
Location	16q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000091651
Ensembl biotype	protein_coding
OMIM	607213
Entrez	23594

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000219097, ENST00000563306, ENST00000563599, ENST00000566860, ENST00000567000, ENST00000568364, ENST00000569239, ENST00000570260, ENST00000575571, ENST00000912415, ENST00000912416, ENST00000912417, ENST00000912418, ENST00000942255

RefSeq mRNA: 1 — MANE Select: NM_014321 NM_014321

CCDS: CCDS10722

Canonical transcript exons

ENST00000219097 — 7 exons

Exon	Start	End
ENSE00000945060	46689659	46689770
ENSE00001203166	46697458	46698394
ENSE00003465011	46693093	46693182
ENSE00003538041	46692382	46692545
ENSE00003569451	46690991	46691120
ENSE00003638833	46696017	46696085
ENSE00003659563	46695562	46695674

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 98.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.1771 / max 324.3729, expressed in 1625 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153917	17.3599	1611
153916	0.8172	498

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.34	gold quality
endothelial cell	CL:0000115	97.69	gold quality
secondary oocyte	CL:0000655	97.43	gold quality
colonic epithelium	UBERON:0000397	92.62	gold quality
right testis	UBERON:0004534	92.57	gold quality
ventricular zone	UBERON:0003053	92.28	gold quality
left testis	UBERON:0004533	92.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.05	gold quality
testis	UBERON:0000473	90.91	gold quality
embryo	UBERON:0000922	90.65	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.51	gold quality
ganglionic eminence	UBERON:0004023	90.45	gold quality
cervix squamous epithelium	UBERON:0006922	90.42	gold quality
trabecular bone tissue	UBERON:0002483	89.95	gold quality
sperm	CL:0000019	88.19	gold quality
bone marrow	UBERON:0002371	87.55	gold quality
tonsil	UBERON:0002372	86.88	gold quality
male germ cell	CL:0000015	85.73	gold quality
bone marrow cell	CL:0002092	85.08	gold quality
gingival epithelium	UBERON:0001949	85.03	gold quality
squamous epithelium	UBERON:0006914	84.85	gold quality
mucosa of transverse colon	UBERON:0004991	84.62	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.56	gold quality
esophagus squamous epithelium	UBERON:0006920	84.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.75	gold quality
superior surface of tongue	UBERON:0007371	82.70	gold quality
adult organism	UBERON:0007023	82.44	gold quality
right adrenal gland cortex	UBERON:0035827	82.44	gold quality
adrenal tissue	UBERON:0018303	82.31	gold quality
right adrenal gland	UBERON:0001233	82.21	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7606	yes	148.90
E-ANND-3	yes	6.18
E-GEOD-111727	no	2379.74
E-MTAB-7052	no	246.10
E-CURD-112	no	2.07
E-MTAB-5061	no	1.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting ORC6, 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-548P	99.98	72.25	3784
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-573	99.55	67.44	955
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-499B-5P	98.35	68.39	988
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-12116	97.94	68.91	595
HSA-MIR-4494	97.86	64.93	850
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-4661-3P	96.81	66.02	342

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 21)

• Functional studies of the Drosophila homolog (PMID:11593009)
• results implicate Orc6 as an essential gene that coordinates chromosome replication and segregation with cytokinesis (PMID:12169736)
• 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)
• Orc6 has a role in sensitizing human colon cancer cells to 5-fluorouracil and cisplatin (PMID:19112505)
• In a cross-species complementation experiment, the expression of human Orc6 in Drosophila Orc6 mutant cells rescued DNA replication, suggesting that this function of the protein is conserved among metazoans. (PMID:19541634)
• findings show that Orc6 not only interacts with Orc1-Orc5 but also with the initiation factor Cdc6, and that Orc6 functions at different stages of the replication initiation process. (PMID:21461783)
• Structural analysis of human Orc6 protein reveals a homology with transcription factor TFIIB. (PMID:21502537)
• our results suggest that Meier-Gorlin syndrome mutations in Orc6 impair the formation of ORC hexamers, interfering with appropriate ORC functions (PMID:24137536)
• The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation. (PMID:25691413)
• The 11-year-old boy with Meier-Gorlin syndrome (MGS) has a homozygous mutation in origin recognition complex, subunit 6 (ORC6) gene mapped to chromosome 16, and his father with heterozygote carrier of ORC6 gene. (PMID:28186598)
• Structural basis of DNA replication origin recognition by human Orc6 protein binding with DNA. (PMID:32986843)
• Humanized Drosophila Model of the Meier-Gorlin Syndrome Reveals Conserved and Divergent Features of the Orc6 Protein. (PMID:33037049)
• Orc6 is a component of the replication fork and enables efficient mismatch repair. (PMID:35622890)
• ORC6, a novel prognostic biomarker, correlates with T regulatory cell infiltration in prostate adenocarcinoma: a pan-cancer analysis. (PMID:36978046)
• DNA Damage-Induced, S-Phase Specific Phosphorylation of Orc6 is Critical for the Maintenance of Genome Stability. (PMID:37096556)
• Multi-omics analysis reveals the involvement of origin recognition complex subunit 6 in tumor immune regulation and malignant progression. (PMID:37901236)
• Long Non-coding RNA COX10-AS1 Promotes Glioma Progression by Competitively Binding miR-1-3p to Regulate ORC6 Expression. (PMID:38244670)
• Phosphorylation of Orc6 During Mitosis Regulates DNA Replication and Ribosome Biogenesis. (PMID:38867464)
• A miR-361-5p/ ORC6/ PLK1 axis regulates prostate cancer progression. (PMID:38885805)
• Origin recognition complex 6 overexpression promotes growth of glioma cells. (PMID:38971772)
• Functional studies of the yeast homolog (PMID:8266075)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	orc6	ENSDARG00000075682
mus_musculus	Orc6	ENSMUSG00000031697
rattus_norvegicus	Orc6	ENSRNOG00000024043
drosophila_melanogaster	Orc6	FBGN0023180

Protein

Protein identifiers

Origin recognition complex subunit 6 — Q9Y5N6 (reviewed: Q9Y5N6)

All UniProt accessions (4): Q9Y5N6, H3BMA4, H3BT22, H3BTQ7

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. Does not bind 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.

Subcellular location. Nucleus.

Disease relevance. Meier-Gorlin syndrome 3 (MGORS3) [MIM:613803] 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 ORC6 family.

RefSeq proteins (1): NP_055136* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008721	ORC6_cyclin_first	Domain
IPR020529	ORC6_met/pln	Family
IPR054113	ORC6_cyclin-like_2nd	Domain

Pfam: PF05460, PF21913

Enzyme classification (BRENDA):

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

UniProt features (31 total): helix 15, strand 4, mutagenesis site 3, sequence variant 3, modified residue 2, chain 1, region of interest 1, compositionally biased region 1, cross-link 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3M03	X-RAY DIFFRACTION	2.5
8S0B	ELECTRON MICROSCOPY	3.6
8S0D	ELECTRON MICROSCOPY	3.6
6KVG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5N6-F1	81.69	0.57

Functional residue map

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

Post-translational modifications (3): 195, 229, 210

Mutagenesis-validated functional residues (3):

Position	Phenotype
137	abolished dna binding.
168	abolished dna binding.
129	abolished dna binding.

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: 423 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, REACTOME_DNA_REPLICATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, WEI_MYCN_TARGETS_WITH_E_BOX, MUELLER_PLURINET, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, DODD_NASOPHARYNGEAL_CARCINOMA_UP, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, VANTVEER_BREAST_CANCER_POOR_PROGNOSIS, FISCHER_DREAM_TARGETS, BASAKI_YBX1_TARGETS_UP

GO Biological Process (3): DNA replication initiation (GO:0006270), DNA replication (GO:0006260), DNA-templated DNA replication (GO:0006261)

GO Molecular Function (2): DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): origin recognition complex (GO:0000808), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear origin of replication recognition complex (GO:0005664), cytosol (GO:0005829), membrane (GO:0016020)

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	4
DNA metabolic process	2
DNA-templated DNA replication	1
DNA biosynthetic process	1
DNA replication	1
nucleic acid binding	1
binding	1
chromosome	1
protein-containing complex	1
nucleolus	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

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORC6	ORC5	O43913	998
ORC6	ORC4	O43929	998
ORC6	CDC6	Q99741	989
ORC6	ORC3	Q9UBD5	989
ORC6	CDT1	Q9H211	982
ORC6	ORC1	Q13415	980
ORC6	ORC2	Q13416	957
ORC6	CDC45	O75419	888
ORC6	MCM5	P33992	746
ORC6	GMNN	O75496	745
ORC6	MCM3	P25205	735
ORC6	MCM4	P33991	732
ORC6	MCM10	Q7L590	729
ORC6	MCM7	P33993	686
ORC6	MCM6	Q14566	649

IntAct

39 interactions, top by confidence:

A	B	Type	Score
ORC2	ORC5	psi-mi:“MI:0914”(association)	0.810
LHX4	ORC6	psi-mi:“MI:0915”(physical association)	0.780
ORC6	LHX4	psi-mi:“MI:0915”(physical association)	0.780
PYGO1	BCL9	psi-mi:“MI:0914”(association)	0.700
ORC6	SPAG5	psi-mi:“MI:0915”(physical association)	0.670
SPAG5	ORC6	psi-mi:“MI:0915”(physical association)	0.670
ORC6	ORC3	psi-mi:“MI:0407”(direct interaction)	0.660
ORC6	ORC3	psi-mi:“MI:0915”(physical association)	0.660
ORC4	ORC6	psi-mi:“MI:0407”(direct interaction)	0.610
ORC6	ORC4	psi-mi:“MI:0407”(direct interaction)	0.610
HMGA1	ORC6	psi-mi:“MI:0915”(physical association)	0.600
HMGA1	ORC6	psi-mi:“MI:0407”(direct interaction)	0.600
ORC6	HMGA1	psi-mi:“MI:0915”(physical association)	0.600
ORC3	ORC4	psi-mi:“MI:0914”(association)	0.590
ORC3	ORC5	psi-mi:“MI:0914”(association)	0.590
CDT1	NDC80	psi-mi:“MI:0914”(association)	0.570
ORC6	DCTN6	psi-mi:“MI:0914”(association)	0.530
ENG	ORC6	psi-mi:“MI:0407”(direct interaction)	0.440
ORC6	MCM2	psi-mi:“MI:0407”(direct interaction)	0.440
ORC6	MCM6	psi-mi:“MI:0407”(direct interaction)	0.440
ORC6	MCM4	psi-mi:“MI:0407”(direct interaction)	0.440
ORC6	CDC7	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (92): ORC6 (Two-hybrid), LHX4 (Two-hybrid), LRWD1 (Affinity Capture-MS), SFPQ (Affinity Capture-MS), PSPC1 (Affinity Capture-MS), BICD2 (Affinity Capture-MS), ORC2 (Affinity Capture-MS), ACTR10 (Affinity Capture-MS), CREB1 (Affinity Capture-MS), DCTN6 (Affinity Capture-MS), PPIL4 (Affinity Capture-MS), ORC6 (Affinity Capture-MS), ORC6 (Affinity Capture-MS), ORC2 (Affinity Capture-MS), BICD2 (Affinity Capture-MS)

ESM2 similar proteins: A2XDG4, A2YNY4, A2YXJ7, A3AF13, A7P514, A9UL13, A9UL14, B1ABR6, B1ABS0, B9GLX8, B9SVG9, O23052, O48653, O81787, O82677, P08240, P48724, Q0WL81, Q29S07, Q2ABE5, Q2HJF3, Q2R374, Q2RAC5, Q3LXA7, Q3UAW9, Q4JF75, Q4R318, Q4V8D6, Q64MA3, Q66IW8, Q66WV0, Q84QM3, Q8GSL4, Q8H252, Q8S8L9, Q8W5R1, Q8W5S1, Q9C8F1, Q9FVS2, Q9HAW0

Diamond homologs: A2YNY4, Q2HJF3, Q8GSL4, Q9WUJ8, Q9Y5N6, Q9ZVH3, Q9Y1B2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ORC6	“form complex”	ORC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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	11	170.9×	2e-21
Activation of ATR in response to replication stress	10	143.1×	9e-19
DNA Replication Pre-Initiation	7	105.7×	4e-12
Switching of origins to a post-replicative state	6	85.9×	5e-10
Synthesis of DNA	6	85.9×	5e-10
Orc1 removal from chromatin	10	85.0×	2e-16
DNA Replication	7	79.3×	3e-11
G1/S Transition	7	77.7×	3e-11

GO biological processes:

GO term	Partners	Fold	FDR
regulation of DNA-templated DNA replication initiation	5	210.7×	1e-09
DNA replication initiation	8	199.7×	2e-15
DNA replication	6	39.6×	3e-07
cell division	5	9.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	4
Uncertain significance	86
Likely benign	56
Benign	9

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1173059	NM_014321.4(ORC6):c.71C>T (p.Ala24Val)	Pathogenic
1173060	NM_014321.4(ORC6):c.65G>A (p.Arg22Lys)	Pathogenic
1924543	NM_014321.4(ORC6):c.49G>T (p.Glu17Ter)	Pathogenic
1975644	NM_014321.4(ORC6):c.509del (p.Ala170fs)	Pathogenic
253274	NM_014321.4(ORC6):c.602_605del (p.Lys201fs)	Pathogenic
2771623	NM_014321.4(ORC6):c.173G>A (p.Trp58Ter)	Pathogenic
30655	NM_014321.4(ORC6):c.257_258del (p.Ser85_Phe86insTer)	Pathogenic
30656	NM_014321.4(ORC6):c.695A>C (p.Tyr232Ser)	Pathogenic
3664050	NM_014321.4(ORC6):c.352del (p.Ile117_Leu118insTer)	Pathogenic
436124	NM_014321.4(ORC6):c.1A>G (p.Met1Val)	Pathogenic
4753961	NM_014321.4(ORC6):c.214del (p.Ser72fs)	Pathogenic
4804790	NM_014321.4(ORC6):c.440C>G (p.Ser147Ter)	Pathogenic
3699362	NM_014321.4(ORC6):c.359+1G>A	Likely pathogenic
4698500	NM_014321.4(ORC6):c.65+2T>C	Likely pathogenic
632252	NM_014321.4(ORC6):c.196-1G>A	Likely pathogenic
977909	NM_014321.4(ORC6):c.360-1G>T	Likely pathogenic

SpliceAI

1047 predictions. Top by Δscore:

Variant	Effect	Δscore
16:46689766:CTGAG:C	donor_loss	1.0000
16:46689768:GAGGT:G	donor_loss	1.0000
16:46689769:AGGTG:A	donor_loss	1.0000
16:46689771:GTG:G	donor_loss	1.0000
16:46689772:T:A	donor_loss	1.0000
16:46689773:GAG:G	donor_loss	1.0000
16:46695673:CA:C	donor_gain	1.0000
16:46695675:G:GG	donor_gain	1.0000
16:46695946:T:TA	acceptor_gain	1.0000
16:46695958:T:G	acceptor_gain	1.0000
16:46697441:T:TA	acceptor_gain	1.0000
16:46697445:A:AG	acceptor_gain	1.0000
16:46697456:A:AG	acceptor_gain	1.0000
16:46697457:G:GG	acceptor_gain	1.0000
16:46697457:GAA:G	acceptor_gain	1.0000
16:46690989:A:AG	acceptor_gain	0.9900
16:46690990:G:GG	acceptor_gain	0.9900
16:46691121:G:GA	donor_loss	0.9900
16:46691122:T:TC	donor_loss	0.9900
16:46693183:G:GG	donor_gain	0.9900
16:46695557:TGTA:T	acceptor_loss	0.9900
16:46695558:GTA:G	acceptor_loss	0.9900
16:46695559:TA:T	acceptor_loss	0.9900
16:46695560:A:AG	acceptor_gain	0.9900
16:46695560:AG:A	acceptor_gain	0.9900
16:46695561:G:GG	acceptor_gain	0.9900
16:46695561:GG:G	acceptor_gain	0.9900
16:46695671:GACA:G	donor_gain	0.9900
16:46695672:ACA:A	donor_gain	0.9900
16:46695672:ACAG:A	donor_loss	0.9900

AlphaMissense

1639 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:46691076:T:C	C51R	0.977
16:46692491:C:A	A102D	0.977
16:46697534:A:C	K236N	0.971
16:46697534:A:T	K236N	0.971
16:46697529:T:A	W235R	0.970
16:46697529:T:C	W235R	0.970
16:46697531:G:C	W235C	0.970
16:46697531:G:T	W235C	0.970
16:46691071:T:A	V49D	0.969
16:46693161:C:A	A143D	0.969
16:46690995:G:C	A24P	0.965
16:46693151:T:C	F140L	0.965
16:46693153:C:A	F140L	0.965
16:46693153:C:G	F140L	0.965
16:46693175:G:C	A148P	0.965
16:46691086:T:C	L54P	0.964
16:46693167:T:C	L145P	0.960
16:46691078:C:G	C51W	0.959
16:46693164:C:A	A144E	0.959
16:46691080:T:C	L52P	0.956
16:46691091:G:C	A56P	0.956
16:46693152:T:C	F140S	0.956
16:46693160:G:C	A143P	0.956
16:46691089:C:A	A55E	0.955
16:46692421:T:G	Y79D	0.954
16:46693176:C:A	A148E	0.953
16:46691061:A:C	S46R	0.952
16:46691063:C:A	S46R	0.952
16:46691063:C:G	S46R	0.952
16:46695648:T:C	L179P	0.951

dbSNP variants (sampled 300 via entrez): RS1000168667 (16:46691799 A>C), RS1000426565 (16:46692891 G>GA,GC,GT), RS1000502102 (16:46693311 A>G), RS1000537397 (16:46698563 T>C), RS1000746405 (16:46698797 A>G,T), RS1001144196 (16:46689865 G>A,C,T), RS1001175364 (16:46690137 A>G), RS1001812983 (16:46691936 A>G), RS1001868451 (16:46692335 A>G), RS1002486757 (16:46695117 GAA>G), RS1003489996 (16:46688902 C>G,T), RS1003725913 (16:46696179 A>T), RS1003898738 (16:46696326 C>A,T), RS1004098702 (16:46695791 G>A), RS1004101222 (16:46695904 T>C)

Disease associations

OMIM: gene MIM:607213 | disease phenotypes: MIM:613803

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 3	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 3	Definitive	AR

Mondo (2): Meier-Gorlin syndrome 3 (MONDO:0013430), Meier-Gorlin syndrome (MONDO:0016817)

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

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000308	Microretrognathia
HP:0000325	Triangular face
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:0000413	Atresia of the external auditory canal
HP:0000426	Prominent nasal bridge
HP:0000494	Downslanted palpebral fissures
HP:0000750	Delayed speech and language development
HP:0000772	Abnormal rib morphology
HP:0000773	Short ribs
HP:0000774	Narrow chest

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

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects expression, decreases expression	4
sodium arsenite	increases expression, affects binding, increases reaction	3
bisphenol A	affects cotreatment, decreases expression	2
Cannabidiol	increases expression, decreases expression	2
Aflatoxin B1	affects expression, increases expression	2
Particulate Matter	affects cotreatment, increases expression, decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
afuresertib	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	decreases expression, affects cotreatment	1
dicrotophos	decreases expression	1
tungsten carbide	affects cotreatment, increases expression	1
bufotalin	increases expression	1
propionaldehyde	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
2-palmitoylglycerol	increases expression	1
GW 4064	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
GW 3965	decreases expression	1
bisphenol S	decreases expression, affects cotreatment	1
jinfukang	increases 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