MCM6

Summary

MCM6 (minichromosome maintenance complex component 6, HGNC:6949) is a protein-coding gene on chromosome 2q21.3, encoding DNA replication licensing factor MCM6 (Q14566). Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells. It is a selective cancer dependency (DepMap: 88.9% of cell lines).

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 4 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of the complex by CDC2 kinase reduces the helicase activity, suggesting a role in the regulation of DNA replication. Single nucleotide polymorphisms in the intron regions of this gene are associated with differential transcriptional activation of the promoter of the neighboring lactase gene and, thereby, influence lactose intolerance in early adulthood.

Source: NCBI Gene 4175 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 166 total
• Phenotypes (HPO): 9
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 88.9% of screened cell lines
• MANE Select transcript: NM_005915

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6949
Approved symbol	MCM6
Name	minichromosome maintenance complex component 6
Location	2q21.3
Locus type	gene with protein product
Status	Approved
Aliases	Mis5
Ensembl gene	ENSG00000076003
Ensembl biotype	protein_coding
OMIM	601806
Entrez	4175

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000264156, ENST00000483902, ENST00000492091, ENST00000884967, ENST00000884968, ENST00000939152, ENST00000939153, ENST00000939154, ENST00000939155, ENST00000939156, ENST00000943622, ENST00000943623

RefSeq mRNA: 1 — MANE Select: NM_005915 NM_005915

CCDS: CCDS2179

Canonical transcript exons

ENST00000264156 — 17 exons

Exon	Start	End
ENSE00000455012	135866563	135866728
ENSE00000455013	135866132	135866277
ENSE00000455018	135856728	135856883
ENSE00000776748	135852787	135852915
ENSE00000776821	135857897	135858004
ENSE00000776862	135859301	135859442
ENSE00000776968	135865013	135865163
ENSE00000776995	135868611	135868860
ENSE00000777053	135870251	135870361
ENSE00000777061	135872697	135872843
ENSE00000827135	135876259	135876443
ENSE00000964124	135844545	135844684
ENSE00001263533	135839626	135840951
ENSE00003484158	135848053	135848188
ENSE00003495079	135846237	135846392
ENSE00003580312	135862607	135862748
ENSE00003648778	135851402	135851563

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7787 / max 344.8437, expressed in 1792 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30772	25.0578	1787
30773	1.7209	902

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.17	gold quality
endometrium epithelium	UBERON:0004811	96.52	gold quality
embryo	UBERON:0000922	96.08	gold quality
ganglionic eminence	UBERON:0004023	95.61	gold quality
trabecular bone tissue	UBERON:0002483	94.76	gold quality
endothelial cell	CL:0000115	94.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.13	gold quality
renal glomerulus	UBERON:0000074	93.67	gold quality
secondary oocyte	CL:0000655	93.58	gold quality
metanephric glomerulus	UBERON:0004736	93.37	gold quality
oocyte	CL:0000023	92.90	gold quality
bone marrow	UBERON:0002371	92.71	gold quality
bone element	UBERON:0001474	92.64	gold quality
thymus	UBERON:0002370	91.88	gold quality
jejunal mucosa	UBERON:0000399	90.82	gold quality
skin of hip	UBERON:0001554	90.54	gold quality
vermiform appendix	UBERON:0001154	89.43	gold quality
cortical plate	UBERON:0005343	89.29	gold quality
oral cavity	UBERON:0000167	89.17	gold quality
bone marrow cell	CL:0002092	88.96	gold quality
cartilage tissue	UBERON:0002418	88.72	gold quality
calcaneal tendon	UBERON:0003701	88.56	gold quality
caecum	UBERON:0001153	88.43	gold quality
upper leg skin	UBERON:0004262	88.24	gold quality
stromal cell of endometrium	CL:0002255	88.23	gold quality
lymph node	UBERON:0000029	87.95	gold quality
mucosa of transverse colon	UBERON:0004991	87.91	gold quality
esophagus squamous epithelium	UBERON:0006920	87.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.86	gold quality
gingival epithelium	UBERON:0001949	87.84	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-ENAD-20	yes	483.76
E-GEOD-99795	yes	293.77
E-MTAB-10662	yes	153.21
E-MTAB-7051	yes	114.24
E-MTAB-6911	no	793.33
E-CURD-11	no	464.88
E-CURD-114	no	95.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, MYCN, NOTCH1, RBPJ

miRNA regulators (miRDB)

64 targeting MCM6, 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-4776-3P	100.00	68.73	1340
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-3153	99.55	67.59	2337

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 88.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 35)

• The subtype and MCM6 protein expression in craniopharyngiomas are related to the prognosis of tumor. (PMID:17294730)
• It was found that the MCM6 label index (LI) was significantly higher in adamantine epithelioma than squamous papillary tumor, and in both primary tumor subtypes the LIs of tumors with recurrence were higher than those without recurrence. (PMID:17410335)
• Data show that cells subjected to chronic hypoxia the replicative restart was inhibited along with numerous replication factors including MCM6 and RPA, and cells reoxygenated after acute hypoxia underwent rapid p53-dependent apoptosis. (PMID:20103649)
• The numbers of the three genotypic combinations reveal that the percentage of this population that is genetically lactose intolerant is 8.23% and that the allele frequencies found are consistent with the expected Mendelian distribution. (PMID:20173814)
• the molecular mechanism of Mcm2-7 chromatin loading and prereplicative complex assembly. (PMID:20202939)
• Results indicate that the interaction between hCdt1 and hMcm6 through their interacting domains is key for hCdt1 in facilitating the MCM hetero-hexamer to load onto chromatin for replication licensing. (PMID:21099365)
• Mcm2-7 loads onto origins during initiation as a double hexamer, yet does not act as a double-stranded DNA pump during elongation. (PMID:22918583)
• Report presence of homozygous–13910CC genetic variant in the MCM-6 gene upstream from the lactase gene in lactose intolerant patients treated with lactose-restricted diet. (PMID:25651706)
• Purified MCM4/6/7 complex containing the G364R MCM4 exhibited similar levels of single-stranded DNA binding and ATPase activities to the complex containing wild-type MCM4 (PMID:25661590)
• Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma (PMID:26013954)
• Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization. (PMID:27624874)
• This MCM4 mutation affected human MCM4/6/7 complex formation, since the complex containing the mutant MCM4 protein is unstable and the mutant MCM4 protein is tend to be degraded. (PMID:27794528)
• knockdown of MCM2 or MCM6 could significantly inhibit foci forming of MDC1 in TE-1 nuclei in response to bleomycin-induced DNA damage (p < 0.001). This study indicates the direct interaction between MDC1 and MCMs in TE-1 nuclei. (PMID:27908247)
• MCM2-MCM6 complex is required for CHK2 chromatin loading and its phosphorylation to DNA damage response in squamous cell carcinoma cells. (PMID:27964702)
• genetic association studies in population in Western Europe: Data confirm an SNP in MCM6 (rs4988235) is predictive of milk consumption; lack of association of genetically predicted milk consumption with prevention of osteoporosis, ischemic heart disease, or type 2 diabetes suggests few beneficial effects of milk consumption but is more consistent with milk promoting adiposity/overweight. (PMID:28225053)
• MCM6 is a highly reproducible marker of poor prognosis in endometrial cancer (PMID:29243125)
• Our findings indicate that MCM6 predicts poor prognosis and promotes metastasis in HCC. Postoperative serum MCM6 level could be valuable to detect preclinical early recurrence, indicative of a need for more careful surveillance and aggressive therapeutic intervention. (PMID:29357919)
• Patients with IDH1 mutation and low MCM6 expression exhibited the longest survival (PMID:29753008)
• Comparison of Lactase Variant MCM6 -13910 C>T Testing and Self-report of Dairy Sensitivity in Patients With Irritable Bowel Syndrome. (PMID:29912753)
• Data suggest that MCM4 phosphorylation by CDK2 plays role in DNA replication licensing system MCM4/MCM6/MCM7; this phosphorylation interferes with MCM complex function by lowering stability of MCM complex; MCM4 is highly phosphorylated in S phase. (MCM = minichromosome maintenance complex [hexamer of components 4/6/7]; CDK2 = cyclin-dependent kinase-2) (PMID:30184107)
• Study have demonstrated that high expression rates of proliferative markers TOP2A and MCM6 in colorectal cancer is linked to a beneficial patient outcome. According to the general opinion, a high expression rate correlates with a poor patient outcome and study was able to refute this assertion. (PMID:31072339)
• MCM2, MCM4, and MCM6 labeling seems to outperform Ki67 as tools to assess cellular proliferation in breast cancer. The onset of sustained Ki67 expression occurs only in late G1 phase, while MCM can label all proliferative cells during the active phases of cell cycle (PMID:31476594)
• GTSE1, together with CDC20, PCNA, and MCM6, may synergistically promote adverse prognosis in hepatocellular carcinoma by activating cell cycle. (PMID:32082966)
• The impact of MCM6 on hepatocellular carcinoma in a Southern Chinese Zhuang population. (PMID:32403044)
• Minichromosome maintenance 6 complex component identified by bioinformatics analysis and experimental validation in esophageal squamous cell carcinoma. (PMID:32583000)
• High MCM6 Expression as a Potential Prognostic Marker in Clear-cell Renal Cell Carcinoma. (PMID:33402477)
• A novel cell-cycle-regulated interaction of the Bloom syndrome helicase BLM with Mcm6 controls replication-linked processes. (PMID:34370039)
• MCM6 is a critical transcriptional target of YAP to promote gastric tumorigenesis and serves as a therapeutic target. (PMID:36185598)
• Hypoxia Induces Tumor-Derived Exosome SNHG16 to Mediate Nasopharyngeal Carcinoma Progression through the miR-23b-5p/MCM6 Pathway. (PMID:37119503)
• MCM6 promotes intrahepatic cholangiocarcinoma progression by upregulating E2F1 and enhancing epithelial-mesenchymal transition. (PMID:37185675)
• De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues. (PMID:37198333)
• UBE3A and MCM6 synergistically regulate the proliferation and migration of lung adenocarcinoma cells. (PMID:37454373)
• MCM6 Inhibits Decidualization via Cross-Talking with ERK Pathway in Human Endometrial Stromal Cells. (PMID:38347378)
• High MCM6 expression promotes proliferation and correlates with poor prognosis in triple-negative breast cancer. (PMID:38639528)
• In silico functional, structural and pathogenicity analysis of missense single nucleotide polymorphisms in human MCM6 gene. (PMID:38773180)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm6	ENSDARG00000057683
mus_musculus	Mcm6	ENSMUSG00000026355
rattus_norvegicus	Mcm6	ENSRNOG00000003703
drosophila_melanogaster	Mcm6	FBGN0025815
caenorhabditis_elegans		WBGENE00003158

Paralogs (8): MCM2 (ENSG00000073111), MCM5 (ENSG00000100297), MCM4 (ENSG00000104738), MCM9 (ENSG00000111877), MCM3 (ENSG00000112118), MCM8 (ENSG00000125885), MCM7 (ENSG00000166508), MCMDC2 (ENSG00000178460)

Protein

Protein identifiers

DNA replication licensing factor MCM6 — Q14566 (reviewed: Q14566)

Alternative names: p105MCM

All UniProt accessions (1): Q14566

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.

Subunit / interactions. Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5. Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex. May interact with MCM10. Interacts with TIPIN. Interacts with CDT1. Interacts with MCMBP. Interacts with DDI2.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.

Polymorphism. Intronic variations in MCM6 upstream from the LCT gene are associated with adult-type hypolactasia [MIM:223100] leading to lactose intolerance, or with lactase persistance. Lactose intolerance is a normal physiological phenomenon caused by developmental down-regulation of lactase activity during childhood or early adulthood. A non-coding variation in MCM6 affects the transcriptional regulation of the LCT gene resulting in down-regulation of lactase activity. However, the majority of Northern Europeans and some African populations have the ability to maintain lactase activity and digest lactose throughout life (lactase persistence).

Miscellaneous. Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.

Similarity. Belongs to the MCM family.

RefSeq proteins (1): NP_005906* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001208	MCM_dom	Domain
IPR008049	MCM6	Family
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR018525	MCM_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR027925	MCM_N	Domain
IPR031327	MCM	Family
IPR033762	MCM_OB	Domain
IPR041024	Mcm6_C	Domain
IPR041562	MCM_lid	Domain

Pfam: PF00493, PF14551, PF17207, PF17855, PF18263

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (100 total): helix 30, strand 27, binding site 9, modified residue 9, turn 7, sequence variant 6, sequence conflict 4, mutagenesis site 3, short sequence motif 2, chain 1, domain 1, site 1

Structure

Experimental structures (PDB)

30 structures.

PDB	Method	Resolution (Å)
7W1Y	ELECTRON MICROSCOPY	2.59
9E2Z	ELECTRON MICROSCOPY	2.6
7PLO	ELECTRON MICROSCOPY	2.8
8W0F	ELECTRON MICROSCOPY	2.8
8S09	ELECTRON MICROSCOPY	3.1
7PFO	ELECTRON MICROSCOPY	3.2
8S0A	ELECTRON MICROSCOPY	3.2
9CAQ	ELECTRON MICROSCOPY	3.2
9LXD	ELECTRON MICROSCOPY	3.27
6XTX	ELECTRON MICROSCOPY	3.29
22VT	ELECTRON MICROSCOPY	3.3
8B9D	ELECTRON MICROSCOPY	3.4
8W0E	ELECTRON MICROSCOPY	3.4
9VLN	ELECTRON MICROSCOPY	3.42
9UQ0	ELECTRON MICROSCOPY	3.47
8W0I	ELECTRON MICROSCOPY	3.5
8S0B	ELECTRON MICROSCOPY	3.6
8S0D	ELECTRON MICROSCOPY	3.6
8S0E	ELECTRON MICROSCOPY	3.8
8W0G	ELECTRON MICROSCOPY	3.8
9LXF	ELECTRON MICROSCOPY	3.86
9LXE	ELECTRON MICROSCOPY	3.96
9VLW	ELECTRON MICROSCOPY	4.06
8S0F	ELECTRON MICROSCOPY	4.1
9C6G	ELECTRON MICROSCOPY	4.26
7W68	ELECTRON MICROSCOPY	4.4
8RWV	ELECTRON MICROSCOPY	6.68
6XTY	ELECTRON MICROSCOPY	6.77
2KLQ	SOLUTION NMR
2LE8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14566-F1	77.06	0.14

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): 529 (arginine finger)

Ligand- & substrate-binding residues (9): 504; 619; 622; 359; 399; 400; 401; 402; 403

Post-translational modifications (9): 1, 13, 219, 271, 278, 643, 689, 762, 791

Mutagenesis-validated functional residues (3):

Position	Phenotype
757	impairs interaction with ctd1.
763	impairs interaction with ctd1.
766	impairs interaction with ctd1.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-176974	Unwinding of DNA
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-69052	Switching of origins to a post-replicative state
R-HSA-1640170	Cell Cycle
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69002	DNA Replication Pre-Initiation
R-HSA-69190	DNA strand elongation
R-HSA-69206	G1/S Transition
R-HSA-69239	Synthesis of DNA
R-HSA-69242	S Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69306	DNA Replication
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints

MSigDB gene sets: 425 (showing top): GNF2_CKS1B, E2F_Q4, KALMA_E2F1_TARGETS, MORF_DNMT1, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, REACTOME_DNA_REPLICATION, MODULE_52, E2F_Q4_01, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GNF2_MSH2, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, MORF_ESPL1, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, MORF_BUB1

GO Biological Process (5): double-strand break repair via break-induced replication (GO:0000727), DNA replication (GO:0006260), DNA replication initiation (GO:0006270), regulation of DNA-templated DNA replication initiation (GO:0030174), mitotic DNA replication (GO:1902969)

GO Molecular Function (11): DNA helicase activity (GO:0003678), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), DNA binding (GO:0003677), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), single-stranded 3’-5’ DNA helicase activity (GO:1990518)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), MCM complex (GO:0042555), CMG complex (GO:0071162), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
DNA Replication Pre-Initiation	2
Synthesis of DNA	2
Cell Cycle, Mitotic	2
DNA Replication	2
Cell Cycle	2
G2/M Checkpoints	1
DNA strand elongation	1
Switching of origins to a post-replicative state	1
G1/S Transition	1
Mitotic G1 phase and G1/S transition	1
S Phase	1
Cell Cycle Checkpoints	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
ATP-dependent activity	2
cellular anatomical structure	2
double-strand break repair via homologous recombination	1
DNA biosynthetic process	1
DNA-templated DNA replication	1
DNA replication initiation	1
regulation of DNA-templated DNA replication	1
mitotic cell cycle	1
nuclear DNA replication	1
mitotic cell cycle process	1
helicase activity	1
ATP-dependent activity, acting on DNA	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
binding	1
catalytic activity	1
single-stranded DNA helicase activity	1
3’-5’ DNA helicase activity	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
protein-containing complex	1
MCM core complex	1
nuclear chromosome	1
GINS complex	1
DNA replication preinitiation complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2852 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM6	MCM5	P33992	991
MCM6	MCM4	P33991	991
MCM6	MCM3	P25205	991
MCM6	MCM7	P33993	990
MCM6	CDT1	Q9H211	986
MCM6	MCM10	Q7L590	978
MCM6	CDC45	O75419	944
MCM6	CDC6	Q99741	877
MCM6	MCMBP	Q9BTE3	859
MCM6	MCM8	Q9UJA3	825
MCM6	CDC7	O00311	822
MCM6	A0A494C100	A0A494C100	820
MCM6	ORC5	O43913	815
MCM6	GINS3	Q9BRX5	813
MCM6	LCT	P09848	798

IntAct

261 interactions, top by confidence:

A	B	Type	Score
MCM2	MCM6	psi-mi:“MI:0915”(physical association)	0.950
MCM6	MCM2	psi-mi:“MI:0915”(physical association)	0.950
MCM7	MCM4	psi-mi:“MI:0914”(association)	0.930
MCM4	MCM7	psi-mi:“MI:0915”(physical association)	0.930
MCM4	MCM7	psi-mi:“MI:0914”(association)	0.930
MCM2	MCM3	psi-mi:“MI:0915”(physical association)	0.920
MCM2	MCM3	psi-mi:“MI:0914”(association)	0.920
MCMBP	MCM3	psi-mi:“MI:0914”(association)	0.890
MCMBP	MCM3	psi-mi:“MI:0915”(physical association)	0.890
MCM6	MCM7	psi-mi:“MI:0915”(physical association)	0.860
MCMBP	MCM4	psi-mi:“MI:0914”(association)	0.850
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
MCM6	MCM3	psi-mi:“MI:0914”(association)	0.810
MCM7	MCM3	psi-mi:“MI:0914”(association)	0.810
MCM3	MCM6	psi-mi:“MI:0407”(direct interaction)	0.810
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730

BioGRID (493): MCM6 (Affinity Capture-MS), MCM6 (Two-hybrid), MCM6 (Two-hybrid), SNRPB2 (Two-hybrid), MCM10 (Two-hybrid), FAM161A (Two-hybrid), ZBTB9 (Two-hybrid), MCM6 (Affinity Capture-MS), MCM6 (Affinity Capture-MS), MCM6 (Affinity Capture-MS), MCM6 (Affinity Capture-MS), MCM6 (Affinity Capture-MS), MCM6 (Affinity Capture-MS), IL36RN (Two-hybrid), ALS2CR11 (Two-hybrid)

ESM2 similar proteins: A4FUD9, B8AZ99, B8AZX3, F4KAB8, O75001, O80786, P25205, P25206, P29458, P30666, P33992, P34647, P41389, P49718, P49731, P49735, P49736, P49739, P55861, P97310, P97311, Q0DHC4, Q14566, Q28BS0, Q28CM3, Q29JI9, Q2KIZ8, Q43704, Q498J7, Q5FWY4, Q5R8G6, Q5ZMN2, Q61J08, Q62724, Q6DIH3, Q6F353, Q6P1V8, Q6PCI7, Q7Q0Q1, Q7ZXB1

Diamond homologs: A4FUD9, B8AEH3, B8AZ14, B8AZ99, B8AZX3, B8B406, B8BKI8, B8BMI1, B9FKM7, D3ZVK1, E1BPX4, F1M5F3, F1N2W9, F1QDI9, F4KAB8, I0IUP3, I0IUP4, O75001, O80786, P24279, P25205, P25206, P29458, P29469, P29496, P30664, P30665, P30666, P33991, P33992, P33993, P34647, P38132, P40377, P41389, P43299, P49717, P49718, P49731, P49735

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ATR	up-regulates	MCM6	phosphorylation
MCM6	“form complex”	MCM	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 148 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	9	27.4×	2e-08
DNA Replication Pre-Initiation	8	23.7×	8e-08
Switching of origins to a post-replicative state	8	22.5×	1e-07
Synthesis of DNA	8	22.5×	1e-07
DNA Replication	9	20.0×	6e-08
Activation of ATR in response to replication stress	7	19.7×	2e-06
G1/S Transition	9	19.6×	6e-08
Mitotic G1 phase and G1/S transition	10	17.2×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
regulation of DNA-templated DNA replication initiation	6	47.5×	9e-07
DNA replication initiation	6	28.2×	1e-05
heterochromatin formation	8	15.4×	1e-05
nucleosome assembly	14	14.8×	6e-10
regulation of DNA replication	5	13.8×	3e-03
DNA replication	8	9.9×	2e-04
chromatin organization	9	6.7×	1e-03
DNA repair	10	4.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	11
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2362 predictions. Top by Δscore:

Variant	Effect	Δscore
2:135844543:A:AC	donor_gain	1.0000
2:135844544:C:CC	donor_gain	1.0000
2:135844682:CTT:C	acceptor_gain	1.0000
2:135844685:C:CC	acceptor_gain	1.0000
2:135848082:T:TA	donor_gain	1.0000
2:135848097:T:TA	donor_gain	1.0000
2:135848187:ACCT:A	acceptor_loss	1.0000
2:135848188:CCTAA:C	acceptor_loss	1.0000
2:135848189:C:CA	acceptor_loss	1.0000
2:135848189:C:CC	acceptor_gain	1.0000
2:135851401:CCTCA:C	donor_gain	1.0000
2:135852784:TAC:T	donor_loss	1.0000
2:135852786:C:CT	donor_loss	1.0000
2:135856580:A:AC	donor_gain	1.0000
2:135856581:C:CC	donor_gain	1.0000
2:135856581:CTAAA:C	donor_gain	1.0000
2:135856584:AAC:A	donor_gain	1.0000
2:135857892:CATA:C	donor_loss	1.0000
2:135857893:ATAC:A	donor_loss	1.0000
2:135857894:TACC:T	donor_loss	1.0000
2:135857895:A:AC	donor_gain	1.0000
2:135857896:C:CC	donor_gain	1.0000
2:135857896:CCT:C	donor_gain	1.0000
2:135857896:CCTT:C	donor_gain	1.0000
2:135858000:ACACC:A	acceptor_gain	1.0000
2:135858001:CACC:C	acceptor_gain	1.0000
2:135858001:CACCC:C	acceptor_gain	1.0000
2:135858003:CC:C	acceptor_gain	1.0000
2:135858004:CC:C	acceptor_gain	1.0000
2:135858004:CCTG:C	acceptor_loss	1.0000

AlphaMissense

5415 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:135851450:G:C	S623R	1.000
2:135851450:G:T	S623R	1.000
2:135851452:T:G	S623R	1.000
2:135852896:G:T	A549D	1.000
2:135856870:G:T	A495D	1.000
2:135857922:A:T	I482K	1.000
2:135857930:C:A	Q479H	1.000
2:135857930:C:G	Q479H	1.000
2:135857996:A:C	C457W	1.000
2:135857997:C:T	C457Y	1.000
2:135859365:A:T	V433D	1.000
2:135866607:C:T	G246E	1.000
2:135866608:C:A	G246W	1.000
2:135868673:A:G	C185R	1.000
2:135868687:C:T	C180Y	1.000
2:135868688:A:G	C180R	1.000
2:135868752:G:C	C158W	1.000
2:135868754:A:G	C158R	1.000
2:135844555:A:G	L780P	0.999
2:135844558:C:G	R779P	0.999
2:135844597:A:G	L766P	0.999
2:135851439:A:G	L627P	0.999
2:135851457:A:G	L621P	0.999
2:135852897:C:G	A549P	0.999
2:135852908:T:A	D545V	0.999
2:135852908:T:G	D545A	0.999
2:135852909:C:G	D545H	0.999
2:135856759:A:G	L532P	0.999
2:135856847:C:G	A503P	0.999
2:135856850:C:G	A502P	0.999

dbSNP variants (sampled 300 via entrez): RS1000058350 (2:135874950 T>C), RS1000156052 (2:135848568 T>G), RS1000186073 (2:135860318 T>A), RS1000208032 (2:135848200 A>G), RS1000226554 (2:135870875 G>C), RS1000228668 (2:135857938 T>C), RS1000286499 (2:135864153 T>C), RS1000339027 (2:135864343 G>C), RS1000486657 (2:135855395 A>G), RS1000514188 (2:135839642 C>T), RS1000545277 (2:135840013 G>A), RS1000576561 (2:135840238 A>C,G), RS1000587682 (2:135873155 T>C), RS1000694565 (2:135877241 A>G), RS1000730953 (2:135841722 C>G,T)

Disease associations

OMIM: gene MIM:601806 | disease phenotypes: MIM:223100

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (3): lactose intolerance adult type (MONDO:0006065), neurodevelopmental disorder (MONDO:0700092), lactose intolerance (MONDO:0100345)

Orphanet (1): NON RARE IN EUROPE: Lactase non-persistence in adulthood (Orphanet:319681)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0003621	Juvenile onset
HP:0004789	Lactose intolerance
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0025130	Decreased small intestinal mucosa lactase level
HP:0033589	Flatulence

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002783_141	Body mass index	5.000000e-06
GCST002783_328	Body mass index	2.000000e-06
GCST004066_73	Hip circumference	2.000000e-08
GCST004765_18	Total cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	9.000000e-07
GCST010397_20	Gut microbiota (bacterial taxa, rank normal transformation method)	1.000000e-06
GCST011335_2	Body mass index and LDL-C (pairwise)	2.000000e-12
GCST011343_2	Body fat percentage and LDL-C (pairwise)	2.000000e-13
GCST90011899_60	Aspartate aminotransferase levels	2.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007806	total cholesterol change measurement
EFO:0007874	gut microbiome measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007800	body fat percentage
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007787	Lactose Intolerance	C06.405.469.637.506; C16.320.565.202.589; C18.452.603.506; C18.452.648.202.589
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296011 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.46	Kd	342.6	nM	CHEMBL5653589
6.46	ED50	342.6	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 15 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148734: Binding affinity to human MCM6 incubated for 45 mins by Kinobead based pull down assay	kd	0.3427	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression, decreases expression	6
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	6
sodium arsenite	decreases expression, increases expression	3
Estradiol	affects cotreatment, increases expression	3
Cyclosporine	decreases expression	3
Cadmium Chloride	increases abundance, increases palmitoylation, decreases expression, decreases reaction	3
methylselenic acid	decreases expression, affects expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Copper	affects binding, decreases expression	2
Parathion	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Quercetin	decreases expression, increases phosphorylation	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	increases expression, decreases expression, affects cotreatment	2
Aflatoxin B1	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
chlortoluron	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenate	decreases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118785	Binding	Binding affinity to MCM6 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02406469	PHASE4	COMPLETED	Effects Comparison of A1 and A2 Milk on Gastrointestinal Physiology, Symptoms and Cognitive Behavior
NCT02636413	PHASE4	COMPLETED	Evaluation of LacTEST for the Diagnosis of Hypolactasia in Adults and Elderly Patients Presenting With Clinical Symptoms of Lactose Intolerance
NCT02878876	PHASE4	COMPLETED	Incidence of Lactose Intolerance Among Self-reported Lactose Intolerant People
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT01145586	PHASE3	COMPLETED	A Non-inferiority, Multicenter and Randomized, Multiple-Dose Study About a Treatment to Hypolactasia
NCT03597516	PHASE3	COMPLETED	Evaluation of the Efficacy, Durability, Safety, and Tolerability of RP-G28 in Patients With Lactose Intolerance
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT01113619	PHASE2	COMPLETED	Effectiveness, Safety and Tolerability Study of RP-G28 for Symptoms Associated With Lactose Intolerance
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03563846	PHASE1	COMPLETED	Effect of a Standard Meal on the Pharmacokinetic Profile of RP-G28 in Healthy Adult Male and Female Subjects
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers