GeneBe

MCM9

protein-coding

minichromosome maintenance 9 homologous recombination repair factor, the group of MCM family

Gene summary

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. [provided by RefSeq, Nov 2010]

Previous symbols:
  • MCMDC1
  • C6orf61

MANE transcript

NM_017696.3

Inheritance

AR, AD

ClinVar variants

P:13U:163B:43

Top phenotype

Ovarian dysgenesis 4

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr6:118,813,442-118,935,162

External References & Databases

Ensembl (ENSG00000111877)NCBI Gene (254394)OMIM (610098)HGNC:21484GenCCUniProt (Q9NXL9)AlphaFoldClinVar (MCM9)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~121.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary neoplastic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015356

Submitter: PanelApp Australia

premature ovarian failure 10DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044776

Submitter: Ambry Genetics

male infertilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005372

Submitter: Ambry Genetics

46,XX ovarian dysgenesis-short stature syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014520

Submitter: Ambry Genetics

46,XX ovarian dysgenesis-short stature syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014520

Submitter: Ambry Genetics

46,XX ovarian dysgenesis-short stature syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014520

Submitter: Orphanet

46,XX ovarian dysgenesis-short stature syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014520

Submitter: Labcorp Genetics (formerly Invitae)

MCM9-related gametogenic failureDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1060226

Submitter: ClinGen

*MCM9* was first reported in relation to autosomal recessive MCM9-related gametogenic failure in 2014 (Wood-Trageser et al., PMID: 25480036). Variants in *MCM9* have been reported in individuals with the following disease entities: premature ovarian insufficiency (PMID: 25480036), non-obstructive azoospermia (PMID: 36769638), ovarian dysgenesis 4 (OMIM: 616185). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, all of these disease entities have been lumped into one, MCM9-related gametogenic failure (http://purl.obolibrary.org/obo/MONDO_1060226). Nine different predicted nonsense variants that have been reported in twenty probands in nine publications (PMIDs: 31042289, 24580036, 36769638, 30406445, 26771056, 32613604, 26806154, 35690514, 40593474) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is supported by animal models and in vitro functional assays. *MCM9* binds to *MCM8* and *HROB*, both being involved in gametogenesis (PMIDs: 37535404, 22771115, 38678026). Absence of *MCM9* causes defects in homologous recombination repair mechanism (PMID: 22771115). Additionally, *MCM9* knockout mice show non-obstructive azoospermia or oligozoospermia in male mice and premature ovarian insufficiency in female mice (PMIDs: 22771120, 21987787). In summary, there is definitive evidence to support the relationship between *MCM9* and autosomal recessive MCM9-related gametogenic failure. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Male Infertility GCEP on the meeting date April 1, 2026 (SOP Version 12).

premature ovarian failure 10LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0044776

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ovarian dysgenesis 4AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Awareness may allow medical management (eg, with combined estrogen-progestin therapy) in order to benefit pubertal development and growth

Refs: 25480036Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCM9 variants in ClinVar

10 Conditions Cataloged
Inborn genetic diseasesTotal: 154
not providedTotal: 34
not specifiedTotal: 24
MCM9-related disorderTotal: 17
46,XX ovarian dysgenesis-short stature syndromeTotal: 14
Premature ovarian failure 1Total: 3
Premature ovarian failureTotal: 1
Non-obstructive azoospermiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017696.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
6
clinvar
13
clinvar
4
clinvar
 23
missense
1
clinvar
150
clinvar
21
clinvar
5
clinvar
 177
nonsense
2
clinvar
3
clinvar
4
clinvar
 9
start loss
0
frameshift
1
clinvar
3
clinvar
1
clinvar
 5
splice donor/acceptor (+/-2bp)
1
clinvar
2
clinvar
2
clinvar
 5
Total49163349219

Highest pathogenic variant AF is 0.000027801665

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_017696.3RefSeqNP_060166.212MANE Select
ENST00000619706.5EnsemblENSP00000480469.112MANE Select
NM_001378356.1RefSeqNP_001365285.112Standard
NM_001378357.1RefSeqNP_001365286.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell Cycle

Biological Process

  • double-strand break repair via homologous recombination
  • DNA replication
  • cellular response to DNA damage stimulus
  • female gamete generation
  • DNA duplex unwinding

Molecular Function

  • DNA binding
  • DNA helicase activity
  • chromatin binding
  • protein binding
  • ATP binding

Cellular Component

  • nucleus
  • chromosome
  • MCM8-MCM9 complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000316316
Coding exons
12
Length
121723
Individuals with no LoFs
125724
Homozygous LoFs
1
Heterozygous LoFs
22
Defined
125747
p
0.0000915
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.454935920.8320.00003087460
Missense (PolyPhen)131186.780.701372412
Synonymous0.7262102240.9380.00001192240
Loss of Function2.242844.00.6360.00000236565

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.000300.00030rare
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.000110.000097rare
South Asian0.000160.00016rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). 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 (PubMed:26215093). Probably by regulating the localization of the MRN complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). Acts as an helicase in DNA mismatch repair (MMR) following DNA replication errors to unwind the mismatch containing DNA strand (PubMed:26300262). In addition, recruits MLH1, a component of the MMR complex, to chromatin (PubMed:26300262). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). Probably by regulating HR, plays a key role during gametogenesis (By similarity). {ECO:0000250|UniProtKB:Q2KHI9, ECO:0000269|PubMed:23401855, ECO:0000269|PubMed:26215093, ECO:0000269|PubMed:26300262}.;
Disease
DISEASE: Ovarian dysgenesis 4 (ODG4) [MIM:616185]: A disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. {ECO:0000269|PubMed:25480036}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
N
Essential (gene trap)
K
Indispensability pred.
N
Indispensability score
0.114

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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