MCM9

Summary

MCM9 (minichromosome maintenance 9 homologous recombination repair factor, HGNC:21484) is a protein-coding gene on chromosome 6q22.31, encoding DNA helicase MCM9 (Q9NXL9). Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR).

The protein encoded by this gene is a member of the mini-chromosome maintenance (MCM) protein family that are essential for the initiation of eukaryotic genome replication. Binding of this protein to chromatin has been shown to be a pre-requisite for recruiting the MCM2-7 helicase to DNA replication origins. This protein also binds, and is a positive regulator of, the chromatin licensing and DNA replication factor 1, CDT1.

Source: NCBI Gene 254394 — RefSeq curated summary.

At a glance

• Gene–disease (curated): premature ovarian failure 10 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 224 total — 3 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 8
• MANE Select transcript: NM_017696

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21484
Approved symbol	MCM9
Name	minichromosome maintenance 9 homologous recombination repair factor
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	MGC35304, dJ329L24.3, FLJ20170
Ensembl gene	ENSG00000111877
Ensembl biotype	protein_coding
OMIM	610098
Entrez	254394

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000316068, ENST00000316316, ENST00000368478, ENST00000425154, ENST00000436788, ENST00000458674, ENST00000505446, ENST00000505485, ENST00000619706, ENST00000877731, ENST00000877732, ENST00000962925

RefSeq mRNA: 17 — MANE Select: NM_017696 NM_001378356, NM_001378357, NM_001378358, NM_001378359, NM_001378360, NM_001378361, NM_001378362, NM_001378363, NM_001378364, NM_001378365, NM_001378366, NM_001378367, NM_001378368, NM_001378369, NM_001378370, NM_017696, NM_153255

CCDS: CCDS5121, CCDS56447

Canonical transcript exons

ENST00000619706 — 14 exons

Exon	Start	End
ENSE00000840059	118913295	118913420
ENSE00000840062	118917561	118917761
ENSE00000840063	118922005	118922086
ENSE00001160217	118923811	118924127
ENSE00001160221	118827927	118828130
ENSE00001512181	118826147	118826292
ENSE00001512182	118826782	118826864
ENSE00001722724	118911650	118911769
ENSE00001774313	118932607	118932740
ENSE00002046152	118931420	118931738
ENSE00003504738	118829048	118829250
ENSE00003683120	118856371	118856545
ENSE00003722076	118813455	118816294
ENSE00003914689	118934891	118935159

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 88.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.5847 / max 114.5880, expressed in 1632 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75309	2.4739	1264
75307	2.1242	852
75308	1.9866	1062

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	88.94	gold quality
bronchial epithelial cell	CL:0002328	86.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.83	gold quality
oocyte	CL:0000023	84.76	gold quality
adrenal tissue	UBERON:0018303	83.41	gold quality
monocyte	CL:0000576	83.28	gold quality
mononuclear cell	CL:0000842	82.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.95	gold quality
calcaneal tendon	UBERON:0003701	82.87	gold quality
leukocyte	CL:0000738	82.73	gold quality
esophagus squamous epithelium	UBERON:0006920	82.69	gold quality
palpebral conjunctiva	UBERON:0001812	82.29	gold quality
sural nerve	UBERON:0015488	82.26	gold quality
epithelium of bronchus	UBERON:0002031	81.78	gold quality
ventricular zone	UBERON:0003053	81.57	gold quality
right uterine tube	UBERON:0001302	80.78	gold quality
bronchus	UBERON:0002185	80.53	gold quality
right lobe of thyroid gland	UBERON:0001119	80.14	gold quality
popliteal artery	UBERON:0002250	79.70	gold quality
tibial artery	UBERON:0007610	79.69	gold quality
left lobe of thyroid gland	UBERON:0001120	79.60	gold quality
rectum	UBERON:0001052	79.46	gold quality
islet of Langerhans	UBERON:0000006	79.13	gold quality
thyroid gland	UBERON:0002046	79.10	gold quality
minor salivary gland	UBERON:0001830	79.07	gold quality
body of pancreas	UBERON:0001150	78.80	gold quality
ganglionic eminence	UBERON:0004023	78.76	gold quality
metanephros cortex	UBERON:0010533	78.73	gold quality
esophagus mucosa	UBERON:0002469	78.69	gold quality
pancreas	UBERON:0001264	78.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

62 targeting MCM9, 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-3162-3P	100.00	65.37	363
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745

Literature-anchored findings (GeneRIF, showing 20)

• Identified a novel MCM family gene, MCM9, by using bioinformatics; mouse MCM9 mRNA was upregulated by transcription factor E2E1 and serum stimulation in NIH3T3 cells. (PMID:15850810)
• We also show that the very recently reported human MCM9 protein (HsMCM9), which resembles a truncated MCM-like protein missing a part of the MCM2-7 signature domain, is an incomplete form of the full length HsMCM9 described here. (PMID:16226853)
• Cdt1, with its two opposing regulatory binding factors MCM9 and geminin, appears to be a major platform on the pre-replication complexes to integrate cell-cycle signals. (PMID:18657502)
• Chromatin immunoprecipitation analysis using human DR-GFP cells demonstrated that MCM8 and MCM9 proteins are rapidly recruited to DNA damage sites and promote RAD51 recruitment. (PMID:23401855)
• A novel alternatively spliced variant of MCM9 is specifically induced after exposure to Mitomycin C. Expression is cell-cycle regulated and induced in S-phase. (PMID:23403237)
• Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. (PMID:25480036)
• MCM9 loading onto chromatin is MSH2-dependent, and in turn MCM9 stimulates the recruitment of MLH1 to chromatin, revealing a role for MCM9 and its helicase activity in DNA mismatch repair. (PMID:26300262)
• Data show that the two affected sisters were homozygous for the mutation of MCM9 gene, encoding the minichromosome maintenance complex component 9. (PMID:26771056)
• Significant number of potentially damaging and novel variants in MCM9 in primary ovarian insufficiency; multiallelic association with variants in DDR and MCM8-MCM9 interactome genes. (PMID:27802094)
• Study identified fifteen variants that included six common SNPs and nine variants of unknown significance (VUS) in MCM9 gene. However VUS occur in MCM9 in a small proportion of Lynch-like syndrome (LLS) patients and MCM9 mutations are unlikely to explain most LLS cases. (PMID:27886675)
• stalled replication forks can be restarted in S phase via homologous recombination using MCM8-9 as an alternative replicative helicase. (PMID:28487407)
• Pathogenic variant in MCM9 gene is associated with premature ovarian insufficiency. (PMID:30406445)
• Conceptual MCM8-9 inhibitors will be powerful cancer-specific chemosensitizers for platinum compounds. (PMID:30648820)
• Novel pathogenic mutations in minichromosome maintenance complex component 9 (MCM9) responsible for premature ovarian insufficiency. (PMID:32145932)
• MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage. (PMID:32528060)
• An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes. (PMID:32613604)
• The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte. (PMID:33750944)
• Structural study of the N-terminal domain of human MCM8/9 complex. (PMID:34043945)
• Activity, substrate preference and structure of the HsMCM8/9 helicase. (PMID:37309874)
• Mechanism of DNA unwinding by MCM8-9 in complex with HROB. (PMID:38678026)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm9	ENSDARG00000013528
mus_musculus	Mcm9	ENSMUSG00000058298
rattus_norvegicus	Mcm9	ENSRNOG00000003281

Paralogs (8): MCM2 (ENSG00000073111), MCM6 (ENSG00000076003), MCM5 (ENSG00000100297), MCM4 (ENSG00000104738), MCM3 (ENSG00000112118), MCM8 (ENSG00000125885), MCM7 (ENSG00000166508), MCMDC2 (ENSG00000178460)

Protein

Protein identifiers

DNA helicase MCM9 — Q9NXL9 (reviewed: Q9NXL9)

Alternative names: DNA 3’-5’ helicase MCM9, Mini-chromosome maintenance deficient domain-containing protein 1, Minichromosome maintenance 9

All UniProt accessions (5): Q9NXL9, A0A0S2Z662, D6RE85, D6RHY8, H0Y6M9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR). The MCM8-MCM9 complex is a 3’-5’ DNA helicase and single-stranded (ss)DNA-stimulated ATPase which binds ssDNA in the presence of nucleoside triphosphates. Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity. Indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs, probably by regulating the localization of the MNR complex. Acts as a helicase in DNA mismatch repair (MMR) following DNA replication errors to unwind the mismatch containing DNA strand. In addition, recruits MLH1, a component of the MMR complex, to chromatin. The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression. Plays a key role during gametogenesis, probably by regulating HR.

Subunit / interactions. Component of the MCM8-MCM9 complex, which forms a heterohexamer with a repeating heterodimer of trimers configuration. Interacts with the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1. Interacts with MLH1; the interaction recruits MLH1 to chromatin. Interacts with MSH2; the interaction recruits MCM9 to chromatin. Interacts with MSH6. Interacts with the MRN complex composed of MRE11, RAD50 and NBN/NBS1; the interaction recruits the MRN complex to DNA damage sites. Interacts with RAD51; the interaction recruits RAD51 to DNA damage sites. Interacts with HROB; the interaction recruits the MCM8-MCM9 complex to DNA damage sites and stimulates the helicase activity.

Subcellular location. Nucleus. Chromosome.

Disease relevance. Ovarian dysgenesis 4 (ODG4) [MIM:616185] A form of ovarian dysgenesis, a disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. ODG4 is an autosomal recessive condition. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The helicase reaction is stimulated by the C-terminal domain of HROB, binding of which changes the conformation of the complex.

Cofactor. Binds 1 Zn(2+) ion per subunit; may also bind Fe(3+) at the same site.

Domain organisation. The ADP-bound heterohexamer forms around a central hole large enough to bind double-stranded (ds)DNA. Has 2 tiers; the N-terminal MCM tier (residues 1-270) and the C-terminal AAA(+) ATPase tier (residues 283-754) joined by a linker which is essential for function. The C-terminal tier rotates compared to the N-terminal tier, which is required for helicase activity. ATP binds in the C-terminal AAA(+) ATPase domain at the boundary between the alternating subunits.

Miscellaneous. Most abundant isoform.

Similarity. Belongs to the MCM family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NXL9-1	L	yes
Q9NXL9-2	M
Q9NXL9-3	S
Q9NXL9-4	4

RefSeq proteins (17): NP_001365285, NP_001365286, NP_001365287, NP_001365288, NP_001365289, NP_001365290, NP_001365291, NP_001365292, NP_001365293, NP_001365294, NP_001365295, NP_001365296, NP_001365297, NP_001365298, NP_001365299, NP_060166, NP_694987 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001208	MCM_dom	Domain
IPR003593	AAA+_ATPase	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031327	MCM	Family
IPR033762	MCM_OB	Domain
IPR041562	MCM_lid	Domain
IPR058768	MCM9_N	Domain

Pfam: PF00493, PF17207, PF17855, PF26066

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (70 total): strand 15, compositionally biased region 8, helix 8, binding site 7, region of interest 6, splice variant 6, mutagenesis site 4, sequence conflict 4, turn 4, modified residue 3, short sequence motif 2, chain 1, domain 1, site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7DPD	X-RAY DIFFRACTION	2.55
8S94	ELECTRON MICROSCOPY	3.94
7YOX	ELECTRON MICROSCOPY	3.95
8S92	ELECTRON MICROSCOPY	4.06
8S91	ELECTRON MICROSCOPY	4.3
7WI7	X-RAY DIFFRACTION	6.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXL9-F1	62.24	0.15

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): 482 (arginine finger)

Ligand- & substrate-binding residues (7): 147; 150; 172; 178; 355; 356; 359

Post-translational modifications (3): 762, 802, 1109

Mutagenesis-validated functional residues (4):

Position	Phenotype
252–254	significantly decreased mcm8-mcm9 helicase activity.
283–287	linker reduction, loss of mcm8-mcm9 helicase activity.
358	loss of helicase activity and dna mismatch repair function but does not affect the interaction with mcm8, msh2 or chroma
482	loss of helicase activity and dna mismatch repair function but does not affect the interaction with mcm8, msh2 or chroma

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 145 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_DNA_DAMAGE_RESPONSE, GOBP_INTERSTRAND_CROSS_LINK_REPAIR, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_FEMALE_GAMETE_GENERATION, GOBP_MISMATCH_REPAIR, GOBP_RECOMBINATIONAL_REPAIR, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_DNA_REPLICATION, GOMF_SINGLE_STRANDED_DNA_BINDING, GOMF_CHROMATIN_BINDING, GOCC_MCM_COMPLEX

GO Biological Process (8): double-strand break repair via homologous recombination (GO:0000724), DNA damage response (GO:0006974), female gamete generation (GO:0007292), recombinational interstrand cross-link repair (GO:0036298), mismatch repair involved in maintenance of fidelity involved in DNA-dependent DNA replication (GO:0070716), protein localization to chromatin (GO:0071168), DNA repair (GO:0006281), gamete generation (GO:0007276)

GO Molecular Function (17): DNA helicase activity (GO:0003678), chromatin binding (GO:0003682), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), MutLbeta complex binding (GO:0032406), MutSalpha complex binding (GO:0032407), MutSbeta complex binding (GO:0032408), 3’-5’ DNA helicase activity (GO:0043138), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), DNA binding (GO:0003677), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), single-stranded DNA helicase activity (GO:0017116)

GO Cellular Component (4): nucleus (GO:0005634), chromosome (GO:0005694), MCM complex (GO:0042555), MCM8-MCM9 complex (GO:0097362)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
mismatch repair complex binding	3
recombinational repair	2
ATP-dependent activity	2
DNA helicase activity	2
double-strand break repair	1
cellular response to stress	1
gamete generation	1
interstrand cross-link repair	1
mismatch repair	1
DNA-templated DNA replication maintenance of fidelity	1
protein localization to chromosome	1
DNA metabolic process	1
DNA damage response	1
sexual reproduction	1
multicellular organismal reproductive 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
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
protein-containing complex	1
MCM core complex	1
MCM complex	1

Protein interactions and networks

STRING

1934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM9	MCM8	Q9UJA3	921
MCM9	A0A494C100	A0A494C100	891
MCM9	CDT1	Q9H211	850
MCM9	MSH2	P43246	764
MCM9	CDC6	Q99741	720
MCM9	MLH1	P40692	716
MCM9	MCM10	Q7L590	714
MCM9	HFM1	A2PYH4	691
MCM9	STAG3	Q9UJ98	641
MCM9	PSMC3IP	Q9P2W1	633
MCM9	MSH3	P20585	623
MCM9	SYCE1	Q8N0S2	621
MCM9	MSH5	O43196	619
MCM9	MSH6	P52701	618
MCM9	E2F4	Q16254	566

IntAct

43 interactions, top by confidence:

A	B	Type	Score
MSH2	MSH3	psi-mi:“MI:0914”(association)	0.920
MCMBP	MCM3	psi-mi:“MI:0914”(association)	0.890
MLH1	PMS1	psi-mi:“MI:0914”(association)	0.830
MSH2	MCM9	psi-mi:“MI:0914”(association)	0.690
MCM9	MLH1	psi-mi:“MI:0915”(physical association)	0.660
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
MCM9	MCM8	psi-mi:“MI:0915”(physical association)	0.640
MCM9	MSH6	psi-mi:“MI:0915”(physical association)	0.620
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
NELFA	IGHMBP2	psi-mi:“MI:0914”(association)	0.530
MSH6	PCNA	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
MCM9	MSH3	psi-mi:“MI:0914”(association)	0.460
MCM9	MCM8	psi-mi:“MI:0915”(physical association)	0.400
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
VWA5A	PIPSL	psi-mi:“MI:0914”(association)	0.350
PLAUR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
HNRNPLL	TBX3	psi-mi:“MI:0914”(association)	0.350
THBS3	APBB1	psi-mi:“MI:0914”(association)	0.350
MCM9	NOP56	psi-mi:“MI:0914”(association)	0.350
MCM9	PSMD14	psi-mi:“MI:0914”(association)	0.350
PNMA2	TARS3	psi-mi:“MI:0914”(association)	0.350
HORMAD2	WASH3P	psi-mi:“MI:0914”(association)	0.350

BioGRID (115): MCM9 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM8 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-MS), MCM9 (Affinity Capture-Western), MSH6 (Affinity Capture-MS), PMS1 (Affinity Capture-MS)

ESM2 similar proteins: A1YFY6, A2T6X9, A6H7I8, B2RUJ5, F1M5F3, F1N2W9, O35430, O35431, O95487, O95628, O95644, P0C6S7, P14316, P17863, P22681, P22682, P23798, P23906, P35227, P81133, P98084, Q02410, Q0IHY4, Q13469, Q14190, Q14432, Q1L994, Q3UR85, Q52L14, Q5CD77, Q5RD33, Q60591, Q61045, Q61079, Q66JB6, Q69ZT9, Q6NRE7, Q6QB00, Q8BIZ1, Q8BT14

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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
Orc1 removal from chromatin	5	33.0×	2e-05
Assembly of the pre-replicative complex	5	25.8×	5e-05
G2/M Checkpoints	5	24.9×	5e-05
DNA Repair	5	18.2×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
mismatch repair	6	97.2×	8e-09
DNA repair	5	8.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	5
Uncertain significance	149
Likely benign	24
Benign	11

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
156587	NM_017696.3(MCM9):c.1732+2T>C	Pathogenic
3254813	NM_017696.3(MCM9):c.672_673delinsC (p.Glu225fs)	Pathogenic
417973	NM_017696.3(MCM9):c.1483G>T (p.Glu495Ter)	Pathogenic
2443172	NM_017696.3(MCM9):c.304+1G>A	Likely pathogenic
3254812	NM_017696.3(MCM9):c.1529-7C>G	Likely pathogenic
3779839	NM_017696.3(MCM9):c.1556G>A (p.Trp519Ter)	Likely pathogenic
3779840	NM_017696.3(MCM9):c.139_140del (p.Leu47fs)	Likely pathogenic
3897556	NM_017696.3(MCM9):c.754C>T (p.Gln252Ter)	Likely pathogenic

SpliceAI

3087 predictions. Top by Δscore:

Variant	Effect	Δscore
6:118826288:CCTCC:C	acceptor_gain	1.0000
6:118826289:CTCCC:C	acceptor_gain	1.0000
6:118826290:TCCCT:T	acceptor_gain	1.0000
6:118826777:CTTAC:C	donor_loss	1.0000
6:118826780:A:AC	donor_gain	1.0000
6:118826780:AC:A	donor_gain	1.0000
6:118826780:ACCTG:A	donor_gain	1.0000
6:118826781:C:CT	donor_gain	1.0000
6:118826781:CC:C	donor_gain	1.0000
6:118826781:CCT:C	donor_gain	1.0000
6:118826781:CCTG:C	donor_gain	1.0000
6:118826781:CCTGC:C	donor_gain	1.0000
6:118826860:ATGAG:A	acceptor_gain	1.0000
6:118826861:TGAG:T	acceptor_gain	1.0000
6:118826862:GAG:G	acceptor_gain	1.0000
6:118826862:GAGC:G	acceptor_loss	1.0000
6:118826863:AG:A	acceptor_gain	1.0000
6:118826863:AGC:A	acceptor_loss	1.0000
6:118826864:GCTAA:G	acceptor_loss	1.0000
6:118826865:C:CC	acceptor_gain	1.0000
6:118826865:CT:C	acceptor_loss	1.0000
6:118826874:C:CT	acceptor_gain	1.0000
6:118827950:T:A	donor_gain	1.0000
6:118829246:CGAGG:C	acceptor_gain	1.0000
6:118829251:C:CC	acceptor_gain	1.0000
6:118829255:C:CT	acceptor_gain	1.0000
6:118829256:A:T	acceptor_gain	1.0000
6:118856370:CCCAG:C	donor_gain	1.0000
6:118856373:AG:A	donor_gain	1.0000
6:118856389:A:AC	donor_gain	1.0000

AlphaMissense

7510 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:118856383:A:T	V438D	1.000
6:118856385:A:C	S437R	1.000
6:118856385:A:T	S437R	1.000
6:118856387:T:G	S437R	1.000
6:118856389:A:T	I436K	1.000
6:118856402:C:T	E432K	1.000
6:118856404:A:T	M431K	1.000
6:118856463:G:C	C411W	1.000
6:118856480:C:G	A406P	1.000
6:118856482:A:G	L405P	1.000
6:118856485:A:T	V404D	1.000
6:118856495:C:A	G401W	1.000
6:118856530:G:T	A389D	1.000
6:118856542:A:G	L385P	1.000
6:118856542:A:T	L385Q	1.000
6:118856545:C:T	G384D	1.000
6:118911745:C:T	G352E	1.000
6:118911746:C:A	G352W	1.000
6:118911746:C:G	G352R	1.000
6:118911746:C:T	G352R	1.000
6:118827933:C:G	A576P	0.999
6:118827946:G:C	S571R	0.999
6:118827946:G:T	S571R	0.999
6:118827948:T:G	S571R	0.999
6:118829122:A:G	L485P	0.999
6:118829125:T:A	D484V	0.999
6:118829127:A:C	F483L	0.999
6:118829127:A:T	F483L	0.999
6:118829129:A:G	F483L	0.999
6:118829133:A:C	S481R	0.999

dbSNP variants (sampled 300 via entrez): RS1000030115 (6:118814539 C>T), RS1000056820 (6:118875867 A>G,T), RS1000066055 (6:118935929 A>C), RS1000068399 (6:118901193 A>G), RS1000070556 (6:118813749 A>G,T), RS1000081099 (6:118894852 C>T), RS1000096777 (6:118936210 C>A,T), RS1000104029 (6:118894157 T>G), RS1000105068 (6:118854366 T>C), RS1000144102 (6:118837455 A>G), RS1000152343 (6:118837317 T>C), RS1000173079 (6:118854884 T>C), RS1000174364 (6:118837419 T>C), RS1000202408 (6:118909486 GT>G,GTT), RS1000266195 (6:118905927 A>G,T)

Disease associations

OMIM: gene MIM:610098 | disease phenotypes: MIM:616185, MIM:311360

GenCC curated gene-disease

Disease	Classification	Inheritance
premature ovarian failure 10	Definitive	Autosomal recessive
46,XX ovarian dysgenesis-short stature syndrome	Strong	Autosomal recessive
hereditary neoplastic syndrome	Strong	Autosomal recessive
male infertility	Limited	Autosomal recessive

Mondo (7): 46,XX ovarian dysgenesis-short stature syndrome (MONDO:0014520), premature ovarian failure 1 (MONDO:0010706), premature menopause (MONDO:0001119), primary ovarian failure (MONDO:0005387), male infertility (MONDO:0005372), premature ovarian failure 10 (MONDO:0044776), hereditary neoplastic syndrome (MONDO:0015356)

Orphanet (3): 46,XX ovarian dysgenesis-short stature syndrome (Orphanet:444048), Fragile X-associated primary ovarian insufficiency (Orphanet:642691), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000786	Primary amenorrhea
HP:0002750	Delayed skeletal maturation
HP:0003621	Juvenile onset
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0008214	Decreased serum estradiol
HP:0008232	Elevated circulating follicle stimulating hormone level

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006427_5	Depression in smokers	1.000000e-06
GCST006624_93	Systolic blood pressure	9.000000e-09
GCST008892_11	Working memory	9.000000e-06
GCST009391_2009	Metabolite levels	9.000000e-06
GCST009524_26	Household income (MTAG)	3.000000e-10
GCST011981_7	Homeostasis model assessment of insulin resistance	1.000000e-06
GCST90002395_486	Mean platelet volume	2.000000e-17

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004335	short-term memory
EFO:0010347	cholesteryl ester 20:3 measurement
EFO:0009695	household income
EFO:0004501	HOMA-IR

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
propionaldehyde	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Aldehydes	decreases expression	1
Caffeine	decreases phosphorylation	1
Endosulfan	increases expression	1
Methyl Methanesulfonate	increases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT01304927	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial
NCT02349945	PHASE2/PHASE3	COMPLETED	FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
NCT05222841	PHASE2/PHASE3	COMPLETED	The Effectiveness of Spermotrend Food Supplement in the Treatment of Male Infertility