GMNN

Summary

GMNN (geminin DNA replication inhibitor, HGNC:17493) is a protein-coding gene on chromosome 6p22.3, encoding Geminin (O75496). Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC).

This gene encodes a protein that plays a critical role in cell cycle regulation. The encoded protein inhibits DNA replication by binding to DNA replication factor Cdt1, preventing the incorporation of minichromosome maintenance proteins into the pre-replication complex. The encoded protein is expressed during the S and G2 phases of the cell cycle and is degraded by the anaphase-promoting complex during the metaphase-anaphase transition. Increased expression of this gene may play a role in several malignancies including colon, rectal and breast cancer. Alternatively spliced transcript variants have been observed for this gene, and two pseudogenes of this gene are located on the short arm of chromosome 16.

Source: NCBI Gene 51053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Meier-Gorlin syndrome 6 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 129 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes — 82 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015895

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17493
Approved symbol	GMNN
Name	geminin DNA replication inhibitor
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Aliases	Gem
Ensembl gene	ENSG00000112312
Ensembl biotype	protein_coding
OMIM	602842
Entrez	51053

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 19 protein_coding, 1 retained_intron

ENST00000230056, ENST00000356509, ENST00000378054, ENST00000378059, ENST00000468943, ENST00000476555, ENST00000620958, ENST00000863462, ENST00000931907, ENST00000931908, ENST00000931909, ENST00000931910, ENST00000931911, ENST00000931912, ENST00000931913, ENST00000931914, ENST00000931915, ENST00000931916, ENST00000931917, ENST00000960430

RefSeq mRNA: 4 — MANE Select: NM_015895 NM_001251989, NM_001251990, NM_001251991, NM_015895

CCDS: CCDS4560

Canonical transcript exons

ENST00000230056 — 7 exons

Exon	Start	End
ENSE00000693554	24780663	24780740
ENSE00000693556	24781477	24781621
ENSE00000693558	24784087	24784169
ENSE00000693560	24784444	24784554
ENSE00000848247	24777222	24777297
ENSE00000848248	24785638	24786099
ENSE00001832686	24774937	24775244

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 98.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.8623 / max 517.2656, expressed in 1812 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66409	38.6731	1812
66410	1.0891	622
66411	0.1002	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.55	gold quality
body of pancreas	UBERON:0001150	98.25	gold quality
secondary oocyte	CL:0000655	97.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.92	gold quality
mucosa of transverse colon	UBERON:0004991	95.70	gold quality
ventricular zone	UBERON:0003053	95.31	gold quality
pancreas	UBERON:0001264	95.18	gold quality
embryo	UBERON:0000922	94.63	gold quality
rectum	UBERON:0001052	94.56	gold quality
ganglionic eminence	UBERON:0004023	94.36	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.22	gold quality
colonic mucosa	UBERON:0000317	94.13	gold quality
palpebral conjunctiva	UBERON:0001812	93.01	gold quality
skin of abdomen	UBERON:0001416	92.63	gold quality
upper leg skin	UBERON:0004262	92.34	gold quality
adrenal tissue	UBERON:0018303	92.15	gold quality
endometrium	UBERON:0001295	91.33	gold quality
trabecular bone tissue	UBERON:0002483	90.71	gold quality
left testis	UBERON:0004533	90.65	gold quality
islet of Langerhans	UBERON:0000006	90.53	gold quality
right testis	UBERON:0004534	90.52	gold quality
prostate gland	UBERON:0002367	90.51	gold quality
testis	UBERON:0000473	90.47	gold quality
transverse colon	UBERON:0001157	90.42	gold quality
sperm	CL:0000019	90.37	gold quality
bone marrow	UBERON:0002371	90.35	gold quality
calcaneal tendon	UBERON:0003701	90.04	gold quality
zone of skin	UBERON:0000014	89.75	gold quality
skin of leg	UBERON:0001511	89.04	gold quality
right uterine tube	UBERON:0001302	88.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	385.76
E-HCAD-5	yes	35.01
E-HCAD-10	yes	25.26
E-GEOD-125970	yes	22.98
E-MTAB-9067	yes	20.76
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, SOX3

miRNA regulators (miRDB)

23 targeting GMNN, 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-4789-5P	99.98	70.76	2721
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-7852-3P	98.37	67.98	823
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-4433A-3P	97.75	62.82	1435
HSA-MIR-4715-5P	97.62	67.47	506
HSA-MIR-4670-3P	97.37	68.35	1378
HSA-MIR-12115	94.19	66.37	738

Literature-anchored findings (GeneRIF, showing 40)

• Results show that geminin, cdt1 and cdc6 are differentially regulated during megakaryocytic differentiation and suggest an active role of cdc6 in endomitosis. (PMID:12429841)
• elevated levels in human cytomegalovirus infected fibroblasts (PMID:12551974)
• Expression and phosphorylation of geminin. (PMID:12745091)
• geminin does not have a role in Cdk-phosphorylation/negative regulation of Cdt1 (PMID:14993212)
• Inactivation of Geminin, an inhibitor of origin licensing, leads to rereplication in human normal and tumor cells within the same cell cycle. (PMID:15159417)
• Geminin is both a negative and positive regulator of pre-replicative complex formation in human cells, playing a positive role in allowing DNA replication factor Double parked accumulation in G2-M (PMID:15257290)
• Data suggest that geminin is required for suppressing overreplication in cells with wild-type or mutant p53 and that a G(2)/M checkpoint restricts the proliferation of cells with overreplicated DNA. (PMID:15282313)
• in proliferating HeLa cells geminin and Cdt1 are co-expressed during a relatively short time at the G(1)-to-S phase transition; Cdt1 is rapidly degraded early in S phase, but geminin remains bound to the chromatin sites (PMID:15284237)
• In situ hybridization and immunohistochemistry localize Cdt1 as well as geminin to the proliferative compartment of the developing mouse gut epithelium (PMID:15291814)
• Results describe the crystal structure of the coiled-coil domain of human geminin, and give a consistent identification and mapping of geminin interacting regions onto structurally important domains. (PMID:15313623)
• expression of geminin is frequently deregulated in tumor cells and might play an important role in the regulation of cell growth in both normal and malignant cells. (PMID:15389519)
• Geminin expression is severely downregulated upon differentiation of Caco-2 cells, an in vitro model of intestinal epithelial differentiation. (PMID:16273206)
• The activity of Gem in regulating cell fate, in addition to its cell-cycle-regulatory activity, requires control of its subcellular localization. (PMID:16464175)
• The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of hepatocellular carcinoma progression in cirrhosis. (PMID:16629645)
• AP4 and geminin act as a repressor complex distinct from REST/NRSF to negatively regulate the expression of target genes in nonneuronal cells. (PMID:16924111)
• Findings suggest that the CDT1 838G/A and GMNN 387C/A polymorphisms may not play a major role in the etiology of breast cancer. (PMID:17029205)
• Geminin is cleaved in primary cells and cancer cell lines induced to undergo apoptosis by a variety of stimuli. (PMID:17261582)
• ATR/Chk1 pathway is activated at an early time point after the loss of Geminin and contributes to checkpoint arrest (PMID:17716975)
• These results suggested that, at least in vitro, oleic acid-containing cell membranes of the lipid bilayer inhibit Cdt1-geminin complex formation by binding to Cdt1 and thereby liberating Cdt1 from inhibition by geminin. (PMID:18288374)
• geminin is overexpressed in human pancreatic cancer and downregulated by apigenin which may contribute to the antitumor effect of this natural flavonoid (PMID:18404646)
• Cdt1 and Geminin expression is deregulated in human tumor specimens and may represent novel markers useful for cancer diagnosis and prognosis. (PMID:18508524)
• PcG complex 1, involving Rae28 and Cdt1, supports the activity of hematopoietic stem cells by enhancing cycling capability and hematopoietic activity through direct regulation of Geminin (PMID:18650381)
• The results of the present study demonstrate that a fraction of geminin is localized on the centrosome, and the centrosomal localization of geminin is Arp1-mediated and dynein-dynactin-dependent. (PMID:18798731)
• Inhibition of geminin activity could be used to selectively kill cancer cells without harming other cells. (PMID:19487297)
• Data show that the Cdt1:Geminin complex can exist in two distinct forms, a “permissive” heterotrimer and an “inhibitory” heterohexamer. (PMID:19906994)
• Geminin expression is potentially a useful marker for predicting tumour aggressiveness and clinical outcome in salivary gland carcinomas. (PMID:20497246)
• Geminin enhances the binding of HDAC11 to Cdt1 and inhibits Cdt1-induced chromatin decondensation. (PMID:20980834)
• Idas as a novel Geminin binding partner, implicated in cell cycle progression, and a putative regulator of proliferation-differentiation decisions during development. (PMID:21543332)
• found that geminin and TopoIIalpha interact primarily in G2/M/early G1 cells on chromosomes, that geminin recruits TopoIIalpha to chromosomal decatenation sites or vice versa and that geminin silencing in mammary epithelial cells triggers formation of chromosome bridges by suppressing TopoIIalpha access to chromosomal arms (PMID:21595939)
• The over-expression of geminin and cdt1 may play an important role in pathogenesis of acute leukemia. (PMID:21729526)
• Geminin has been shown to coordinate proliferation and differentiation by regulating cell cycle progression, chromatin organization, and transcription in the nervous system. (Review) (PMID:21740351)
• geminin is a genuine oncogene that promotes cytokinesis failure and production of aneuploid, aggressive breast tumors when overexpressed (PMID:22184288)
• If cell cycle checkpoints are inhibited in cells lacking geminin, cells progress through mitosis and less re-replication occurs. (PMID:22366459)
• Data suggest that pulmonary metastasis is corrected with levels of Geminin, cleaved caspase-3, CD44, E-cadherin, epidermal growth factor receptor, and CD204 in cancer cells within permeated lymphatic vessels. (PMID:22429811)
• The C-terminal residue Ser184 of Geminin can be phosphorylated by Casein kinase II, resulting in the enhanced binding to Hox and more potent inhibitory effect on Hox transcriptional activity. (PMID:22615398)
• Coincidently amplified CDK13, GMNN, and CENPF genes can play a role as common cancer-driver genes in human cancers. (PMID:22912832)
• Protein levels of Geminin and Cdt1 are tightly regulated through the cell cycle, and the Cdt1-Geminin complex likely acts as a molecular switch that can enable or disable the firing of each origin of replication. (PMID:22918581)
• p53 not only regulates cell-cycle progression, but also functions through geminin to prevent DHFR amplification and protect genomic integrity. (PMID:23026135)
• Data indicate that retroviral transduction-mediated overexpression or siRNA-mediated knock-down of Hoxa9 respectively down-regulated or up-regulated Geminin in hematopoietic cells. (PMID:23326393)
• The Aurora-A-geminin-Cdt1 axis represents a critical regulator of proper DNA replication. (PMID:23695679)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gmnn	ENSDARG00000035957
mus_musculus	Gmnn	ENSMUSG00000006715
rattus_norvegicus	Gmnn	ENSRNOG00000018782
drosophila_melanogaster	geminin	FBGN0033081

Paralogs (2): GMNC (ENSG00000205835), MCIDAS (ENSG00000234602)

Protein

Protein identifiers

Geminin — O75496 (reviewed: O75496)

All UniProt accessions (4): C9K0U5, E2QRF9, O75496, H7C608

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC). It is degraded during the mitotic phase of the cell cycle. Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle. Inhibits histone acetyltransferase activity of KAT7/HBO1 in a CDT1-dependent manner, inhibiting histone H4 acetylation and DNA replication licensing. Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control.

Subunit / interactions. Homotetramer. Interacts with CDT1; this inhibits binding of the MCM complex to origins of replication. The complex with CDT1 exists in two forms, a ‘permissive’ heterotrimer and an ‘inhibitory’ heterohexamer. Interacts (via coiled-coil domain) with IDAS (via coiled-coil domain); this targets GMNN to the nucleus. The heterodimer formed by GMNN and MCIDAS has much lower affinity for CDT1 than the GMNN homodimer. Interacts with a subset of Hox proteins, affinity increasing from anterior to posterior types, the strongest interaction being with HOXB1, HOXC9 and HOXD10. Interacts with LRWD1 from G1/S to mitosis.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated during mitosis. Phosphorylation at Ser-184 by CK2 results in enhanced binding to Hox proteins and more potent inhibitory effect on Hox transcriptional activity.

Disease relevance. Meier-Gorlin syndrome 6 (MGORS6) [MIM:616835] A form of Meier-Gorlin syndrome, 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 geminin family.

RefSeq proteins (4): NP_001238918, NP_001238919, NP_001238920, NP_056979* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022786	Geminin/Multicilin	Family

Pfam: PF07412

UniProt features (25 total): modified residue 7, sequence variant 7, region of interest 4, compositionally biased region 3, chain 1, helix 1, turn 1, coiled-coil region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1T6F	X-RAY DIFFRACTION	1.47
1UII	X-RAY DIFFRACTION	2
4BRY	X-RAY DIFFRACTION	2.89
2WVR	X-RAY DIFFRACTION	3.3
7KLZ	X-RAY DIFFRACTION	3.4
2LP0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75496-F1	70.49	0.30

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 (7): 34, 36, 49, 63, 64, 184, 27

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-69052	Switching of origins to a post-replicative state

MSigDB gene sets: 992 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, ATF_B, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, E2F_Q4_01, HORIUCHI_WTAP_TARGETS_DN, E2F4DP1_01, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, MODULE_255, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, PAL_PRMT5_TARGETS_UP, GOBP_CELL_CYCLE_DNA_REPLICATION, FISCHER_G1_S_CELL_CYCLE, ENK_UV_RESPONSE_KERATINOCYTE_UP

GO Biological Process (12): regulation of DNA replication (GO:0006275), regulation of mitotic cell cycle (GO:0007346), negative regulation of DNA replication (GO:0008156), animal organ morphogenesis (GO:0009887), regulation of DNA-templated DNA replication initiation (GO:0030174), negative regulation of cell cycle (GO:0045786), negative regulation of DNA-templated transcription (GO:0045892), protein-containing complex assembly (GO:0065003), negative regulation of mitotic DNA replication initiation (GO:1903467), negative regulation of DNA-templated DNA replication (GO:2000104), positive regulation of chromatin binding (GO:0035563), DNA replication preinitiation complex assembly (GO:0071163)

GO Molecular Function (5): chromatin binding (GO:0003682), transcription corepressor activity (GO:0003714), histone deacetylase binding (GO:0042826), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), transcription repressor complex (GO:0017053)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
DNA Replication Pre-Initiation	2
G1/S Transition	1
Synthesis of DNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA replication	2
regulation of cell cycle	2
regulation of DNA-templated DNA replication	2
binding	2
regulation of DNA metabolic process	1
mitotic cell cycle	1
regulation of DNA replication	1
negative regulation of DNA metabolic process	1
anatomical structure morphogenesis	1
animal organ development	1
DNA replication initiation	1
cell cycle	1
negative regulation of cellular process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
cellular component assembly	1
protein-containing complex organization	1
negative regulation of DNA-templated DNA replication initiation	1
mitotic DNA replication initiation	1
negative regulation of mitotic cell cycle DNA replication	1
regulation of mitotic DNA replication initiation	1
DNA-templated DNA replication	1
negative regulation of DNA replication	1
chromatin binding	1
positive regulation of binding	1
cell cycle process	1
nuclear DNA replication	1
protein-DNA complex assembly	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
enzyme binding	1
transcription factor binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
transcription regulator complex	1

Protein interactions and networks

STRING

1751 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GMNN	CDT1	Q9H211	982
GMNN	SIX3	O95343	773
GMNN	ORC4	O43929	767
GMNN	ORC6	Q9Y5N6	745
GMNN	FBXO5	Q9UKT4	731
GMNN	CDC6	Q99741	717
GMNN	CDC45	O75419	708
GMNN	FBXO43	Q4G163	683
GMNN	EVI5	O60447	649
GMNN	CDC20	Q12834	640
GMNN	MCM5	P33992	607
GMNN	MCM3	P25205	599
GMNN	MCM6	Q14566	599
GMNN	HOXB9	P17482	585
GMNN	MCM4	P33991	564

IntAct

129 interactions, top by confidence:

A	B	Type	Score
CDT1	GMNN	psi-mi:“MI:0915”(physical association)	0.970
GMNN	CDT1	psi-mi:“MI:0915”(physical association)	0.970
CDT1	GMNN	psi-mi:“MI:0407”(direct interaction)	0.970
GMNN	CDT1	psi-mi:“MI:0407”(direct interaction)	0.970
GMNN	CDT1	psi-mi:“MI:2364”(proximity)	0.970
CDT1	GMNN	psi-mi:“MI:0914”(association)	0.970
GMNN	ZNF439	psi-mi:“MI:0915”(physical association)	0.780
ZNF439	GMNN	psi-mi:“MI:0915”(physical association)	0.780
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
MCIDAS	GMNN	psi-mi:“MI:0915”(physical association)	0.770
GMNN	MCIDAS	psi-mi:“MI:0915”(physical association)	0.770

BioGRID (194): CCDC146 (Two-hybrid), ZNF439 (Two-hybrid), GMNN (Affinity Capture-Western), CDT1 (Affinity Capture-Western), GMNN (Affinity Capture-MS), GMNN (Affinity Capture-MS), GMNN (Affinity Capture-MS), GMNN (Affinity Capture-MS), GMNN (Affinity Capture-MS), GMNN (Affinity Capture-MS), GMNN (Affinity Capture-MS), ZMYM4 (Co-fractionation), GMNN (Proximity Label-MS), ATM (Affinity Capture-MS), CASP8 (Affinity Capture-MS)

ESM2 similar proteins: A0JNH9, A1L162, A2VCV0, A6QQ66, B3NLX1, B4P6W7, B8QB46, O75496, O75971, O88513, P32447, P51860, P53911, P85107, Q03563, Q04996, Q2T9W9, Q3UYG8, Q4VA55, Q5H9M0, Q5RD97, Q5W0B1, Q5ZMS4, Q60524, Q641E3, Q65Z40, Q66H73, Q6AWX6, Q6BKL0, Q6DFV7, Q6KAQ7, Q6PG04, Q6TXG9, Q794H2, Q7X9V2, Q7Z5K2, Q8INT5, Q8IW19, Q8IYH5, Q8L7S0

Diamond homologs: D3ZDX9, D6RGH6, F1SLM8, F7BHS0, G3N1S4, O75496, O88513, Q08B36, Q3UZ45

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
GMNN	“down-regulates activity”	CDT1	binding
SPOP	“down-regulates activity”	GMNN	ubiquitination
ABL1	“up-regulates activity”	GMNN	phosphorylation
AURKA	“up-regulates activity”	GMNN	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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
TP53 Regulates Transcription of Cell Cycle Genes	5	52.3×	5e-06
G1/S Transition	7	31.4×	5e-07
Mitotic G1 phase and G1/S transition	8	28.3×	1e-07
Cyclin D associated events in G1	5	22.4×	1e-04
S Phase	6	20.9×	5e-05
SCF(Skp2)-mediated degradation of p27/p21	5	20.0×	2e-04
Orc1 removal from chromatin	5	17.2×	3e-04
Cellular Senescence	5	13.2×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mitotic cell cycle	5	16.9×	2e-03
Ras protein signal transduction	5	14.5×	2e-03
G1/S transition of mitotic cell cycle	5	14.1×	2e-03
cell division	9	5.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	56
Likely benign	34
Benign	20

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
203999	NM_015895.5(GMNN):c.16A>T (p.Lys6Ter)	Pathogenic
204000	NM_015895.5(GMNN):c.35_38del (p.Ile12fs)	Pathogenic
204001	NM_015895.5(GMNN):c.50A>G (p.Lys17Arg)	Likely pathogenic

SpliceAI

2027 predictions. Top by Δscore:

Variant	Effect	Δscore
6:24777220:A:AG	acceptor_gain	1.0000
6:24777221:G:GA	acceptor_gain	1.0000
6:24780661:A:AG	acceptor_gain	1.0000
6:24780662:G:GG	acceptor_gain	1.0000
6:24780662:GA:G	acceptor_gain	1.0000
6:24780662:GAAT:G	acceptor_gain	1.0000
6:24780662:GAATA:G	acceptor_gain	1.0000
6:24781475:AGCT:A	acceptor_gain	1.0000
6:24781476:G:GT	acceptor_loss	1.0000
6:24781476:GC:G	acceptor_gain	1.0000
6:24781476:GCT:G	acceptor_gain	1.0000
6:24781476:GCTG:G	acceptor_gain	1.0000
6:24781476:GCTGT:G	acceptor_gain	1.0000
6:24781617:TAAAG:T	donor_loss	1.0000
6:24781618:AAAGG:A	donor_loss	1.0000
6:24781619:AAGGT:A	donor_loss	1.0000
6:24781620:AGG:A	donor_loss	1.0000
6:24781621:GGTA:G	donor_loss	1.0000
6:24781622:G:C	donor_loss	1.0000
6:24781623:T:A	donor_loss	1.0000
6:24784085:A:AG	acceptor_gain	1.0000
6:24784086:G:GG	acceptor_gain	1.0000
6:24784086:GAA:G	acceptor_gain	1.0000
6:24784086:GAAA:G	acceptor_gain	1.0000
6:24784158:GAAAA:G	donor_gain	1.0000
6:24784166:GAAA:G	donor_gain	1.0000
6:24784167:A:T	donor_gain	1.0000
6:24784169:AG:A	donor_loss	1.0000
6:24784170:G:GA	donor_loss	1.0000
6:24784170:GTAT:G	donor_gain	1.0000

AlphaMissense

1379 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:24784129:G:C	R106P	0.997
6:24784119:G:C	A103P	0.996
6:24784445:T:C	L120P	0.994
6:24784487:T:C	L134P	0.994
6:24784153:T:C	L114P	0.992
6:24784519:G:C	A145P	0.991
6:24784149:G:C	A113P	0.990
6:24784109:G:C	W99C	0.989
6:24784109:G:T	W99C	0.989
6:24784540:G:C	A152P	0.989
6:24784107:T:A	W99R	0.988
6:24784107:T:C	W99R	0.988
6:24784141:T:C	L110P	0.988
6:24780680:A:C	R23S	0.986
6:24780680:A:T	R23S	0.986
6:24784137:G:C	A109P	0.985
6:24784508:T:C	L141P	0.985
6:24784141:T:A	L110Q	0.984
6:24784105:A:C	Y98S	0.980
6:24784163:T:A	N117K	0.979
6:24784163:T:G	N117K	0.979
6:24780697:T:G	I29S	0.978
6:24784120:C:A	A103E	0.976
6:24780688:T:C	L26P	0.975
6:24780697:T:C	I29T	0.974
6:24784108:G:C	W99S	0.974
6:24784133:A:C	R107S	0.974
6:24784133:A:T	R107S	0.974
6:24780679:G:C	R23T	0.973
6:24780688:T:A	L26Q	0.973

dbSNP variants (sampled 300 via entrez): RS1000060848 (6:24782099 A>C), RS1000390853 (6:24785957 T>C,G), RS1000792627 (6:24777454 T>C), RS1000992664 (6:24784192 A>G), RS1001338585 (6:24784501 A>G), RS1001697160 (6:24783258 T>C), RS1001940177 (6:24783099 C>T), RS1002168858 (6:24776707 C>T), RS1002393981 (6:24782738 T>C), RS1002456409 (6:24776500 T>C), RS1002838404 (6:24780133 C>T), RS1002947149 (6:24773736 G>A), RS1002994006 (6:24781277 A>G), RS1003082372 (6:24774932 T>A,C), RS1003356739 (6:24785470 A>G)

Disease associations

OMIM: gene MIM:602842 | disease phenotypes: MIM:616835, MIM:224690

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 6	Strong	Autosomal dominant
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 6	Moderate	AD

Mondo (2): Meier-Gorlin syndrome 6 (MONDO:0014794), Meier-Gorlin syndrome (MONDO:0016817)

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

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant 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: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:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000430	Underdeveloped nasal alae
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000621	Entropion

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_1847	Metabolite levels	4.000000e-06
GCST009391_2119	Metabolite levels	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010413	triacylglycerol 52:1 measurement
EFO:0010382	phosphatidylcholine 36:4 measurement

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293278 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

82 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 455,023 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL107	COLCHICINE	4	93,932
CHEMBL1082607	SALMETEROL XINAFOATE	4	15,201
CHEMBL1083993	AMIODARONE HYDROCHLORIDE	4	3,265
CHEMBL1116	RALOXIFENE HYDROCHLORIDE	4	28,574
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1200326	NICARDIPINE HYDROCHLORIDE	4	3,903
CHEMBL1200418	DOBUTAMINE HYDROCHLORIDE	4	2,745
CHEMBL1200494	GUANFACINE HYDROCHLORIDE	4	2,675
CHEMBL1200503	BROMOCRIPTINE MESYLATE	4	9,358
CHEMBL1200517	DIHYDROERGOTAMINE MESYLATE	4	2,704
CHEMBL1200561	DOXAZOSIN MESYLATE	4	11,917
CHEMBL1200750	PROMETHAZINE HYDROCHLORIDE	4	9,776
CHEMBL1200916	THIORIDAZINE HYDROCHLORIDE	4	14,243
CHEMBL1201082	FLUOXETINE HYDROCHLORIDE	4	18,871
CHEMBL1201102	TRIFLUPROMAZINE HYDROCHLORIDE	4	606
CHEMBL121663	DEQUALINIUM CHLORIDE	4	4,224
CHEMBL1255654	TETRACAINE HYDROCHLORIDE	4	5,419
CHEMBL1276308	MIFEPRISTONE	4	30,535
CHEMBL1314751	PROCHLORPERAZINE MALEATE	4	4,685
CHEMBL1417019	MITOXANTRONE HYDROCHLORIDE	4
CHEMBL1423	PIMOZIDE	4
CHEMBL1448	NICLOSAMIDE	4
CHEMBL1448187	FLUPHENAZINE HYDROCHLORIDE	4
CHEMBL1480	FELODIPINE	4
CHEMBL1489	AZACITIDINE	4
CHEMBL1523964	EPHEDRINE SULFATE	4
CHEMBL1531864	PIRENZEPINE HYDROCHLORIDE	4
CHEMBL1534525	MIBEFRADIL DIHYDROCHLORIDE	4
CHEMBL1542	AZATHIOPRINE	4

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

ChEMBL bioactivities

102 potent at pChembl≥5 of 309 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.65	Potency	22.4	nM	PACLITAXEL
7.45	Potency	35.5	nM	CHEMBL273648
7.40	Potency	39.8	nM	COLCHICINE
7.35	Potency	44.7	nM	CHEMBL1437846
7.30	Potency	50.1	nM	CHEMBL1554098
6.95	Potency	112.2	nM	OUABAIN
6.80	Potency	158.5	nM	NOCODAZOLE
6.80	Potency	158.5	nM	EMETINE HYDROCHLORIDE
6.80	Potency	158.5	nM	TYRPHOSTIN A9
6.50	Potency	316.2	nM	NICLOSAMIDE
6.50	Potency	316.2	nM	CAMPTOTHECIN
6.05	Potency	891.3	nM	CHEMBL1559663
6.00	Potency	1000	nM	TYRPHOSTIN AG-1478
5.95	Potency	1122	nM	CHEMBL416753
5.95	Potency	1122	nM	CHEMBL1440857
5.95	Potency	1122	nM	BAY-11-7085
5.85	Potency	1412	nM	ROTENONE
5.80	Potency	1585	nM	CALCIMYCIN
5.80	Potency	1585	nM	DIHYDROOUABAIN
5.75	Potency	1778	nM	AZATHIOPRINE
5.75	Potency	1778	nM	CHEMBL1255936
5.70	Potency	1995	nM	CHEMBL8066
5.70	Potency	1995	nM	IDARUBICIN
5.65	Potency	2239	nM	CHEMBL72365
5.65	Potency	2239	nM	CANTHARIDIC_ACID
5.60	Potency	2512	nM	SANGUINARIUM CHLORIDE
5.60	Potency	2512	nM	QUINACRINE DIHYDROCHLORIDE
5.60	Potency	2512	nM	CHEMBL261557
5.60	Potency	2512	nM	CYTARABINE HYDROCHLORIDE
5.55	Potency	2818	nM	CHEMBL293749
5.55	Potency	2818	nM	CHELERYTHRINE CHLORIDE
5.55	Potency	2818	nM	CHEMBL303579
5.55	Potency	2818	nM	CHEMBL1204148
5.50	Potency	3162	nM	TPCK
5.50	Potency	3162	nM	TYRPHOSTIN AG 879
5.50	Potency	3162	nM	CHEMBL47940
5.50	Potency	3162	nM	AZACITIDINE
5.50	Potency	3162	nM	CHEMBL258767
5.50	Potency	3162	nM	CHEMBL285629
5.50	Potency	3162	nM	CHEMBL605003
5.50	Potency	3162	nM	PICEATANNOL
5.50	Potency	3162	nM	GW282974X
5.50	Potency	3162	nM	2-METHOXYESTRADIOL
5.50	Potency	3162	nM	LEFLUNOMIDE
5.50	Potency	3162	nM	CHEMBL1256667
5.50	Potency	3162	nM	CHEMBL1368121
5.50	Potency	3162	nM	BROMOENOL LACTONE
5.45	Potency	3548	nM	CHEMBL1554131
5.45	Potency	3548	nM	CHEMBL1256911
5.45	Potency	3548	nM	CAPSAZEPINE

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
Cyclosporine	decreases expression	4
Acetaminophen	affects expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
chromium hexavalent ion	affects cotreatment, increases ubiquitination, decreases expression, increases abundance	2
Resveratrol	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Genistein	increases expression	2
Particulate Matter	decreases reaction, increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
geraniol	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
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	increases expression	1
coumarin	affects phosphorylation	1
azoxystrobin	increases expression	1
K 7174	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
pyrimidifen	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
palbociclib	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613941	Functional	PUBCHEM_BIOASSAY: Validation screen for small molecules that induce DNA re-replication in MCF 10A normal breast cells. (Class of assay: confirmatory)	PubChem BioAssay data set

Cellosaurus cell lines

15 cell lines: 10 cancer cell line, 2 conditionally immortalized cell line, 2 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1TU	EndoC-betaH2-OFP-GFZ	Conditionally immortalized cell line	Sex unspecified
CVCL_A1TV	EndoC-betaH21-PGF2AOF	Conditionally immortalized cell line	Sex unspecified
CVCL_A7AU	HeLa/Fucci(CA)5	Cancer cell line	Female
CVCL_A7AV	HeLa/Fucci(SA)5	Cancer cell line	Female
CVCL_B1SZ	Abcam HeLa GMNN KO	Cancer cell line	Female
CVCL_E069	NMuMG/Fucci	Spontaneously immortalized cell line	Female
CVCL_E070	HeLa/Fucci	Cancer cell line	Female
CVCL_E071	COS/Fucci	Transformed cell line	Male
CVCL_E0W0	HCT-116 MTBP-mClover-XLoneGemininT25D	Cancer cell line	Male
CVCL_E0W1	HCT-116 TICRR-mClover-XLoneGemininT25D	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry