Premature ovarian failure 10

disease

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Summary

Premature ovarian failure 10 (MONDO:0044776) is a disease caused by variants in MCM9 and MCM8, with 2 cohort genes and 1 clinical trial.

At a glance

Causal genes: MCM9 (GenCC Definitive), MCM8 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 14
Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	premature ovarian failure 10
Mondo ID	MONDO:0044776
OMIM	612885
DOID	DOID:0080867
UMLS	C4225402
MedGen	898849
GARD	0025908
Is cancer (heuristic)	no

Also known as: premature ovarian failure 10

Data availability: 14 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited primary ovarian failure › premature ovarian failure 10

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

14 retrieved; paginated sample, class counts are floors:

6 pathogenic, 4 uncertain significance, 3 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1049848	NM_032485.6(MCM8):c.2059C>T (p.Arg687Ter)	MCM8	Pathogenic	no assertion criteria provided
161191	NM_032485.6(MCM8):c.446C>G (p.Pro149Arg)	MCM8	Pathogenic	no assertion criteria provided
208810	NM_032485.6(MCM8):c.1954-1G>A	MCM8	Pathogenic	no assertion criteria provided
208811	NM_032485.6(MCM8):c.1470_1471insTA (p.Leu491fs)	MCM8	Pathogenic	no assertion criteria provided
2172278	NM_032485.6(MCM8):c.351_354del (p.Lys118fs)	MCM8	Pathogenic	criteria provided, multiple submitters, no conflicts
812137	NM_032485.6(MCM8):c.925C>T (p.Arg309Ter)	MCM8	Pathogenic	criteria provided, single submitter
1214009	NM_032485.6(MCM8):c.1953+1G>C	MCM8	Likely pathogenic	no assertion criteria provided
1328959	NM_032485.6(MCM8):c.482A>C (p.His161Pro)	MCM8	Likely pathogenic	criteria provided, single submitter
2627933	NM_032485.6(MCM8):c.1404C>A (p.Cys468Ter)	MCM8	Likely pathogenic	criteria provided, single submitter
1806488	NM_032485.6(MCM8):c.1033C>T (p.Arg345Ter)	MCM8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1708992	NM_032485.6(MCM8):c.134G>A (p.Gly45Glu)	MCM8	Uncertain significance	criteria provided, single submitter
3779838	NM_032485.6(MCM8):c.1255-475del	MCM8	Uncertain significance	criteria provided, single submitter
812132	NM_032485.6(MCM8):c.89A>C (p.Lys30Thr)	MCM8	Uncertain significance	criteria provided, single submitter
812133	NM_032485.6(MCM8):c.1330A>G (p.Ile444Val)	MCM8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MCM9	Definitive	Autosomal recessive	premature ovarian failure 10	8
MCM8	Strong	Autosomal recessive	premature ovarian failure 10	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCM9	Orphanet:444048	46,XX ovarian dysgenesis-short stature syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MCM8	HGNC:16147	ENSG00000125885	Q9UJA3	DNA helicase MCM8	gencc,clinvar
MCM9	HGNC:21484	ENSG00000111877	Q9NXL9	DNA helicase MCM9	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCM8	DNA helicase MCM8	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).
MCM9	DNA helicase MCM9	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).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCM8	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold
MCM9	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
oocyte	1
primordial germ cell in gonad	1
bronchial epithelial cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCM8	226	ubiquitous	marker	primordial germ cell in gonad, buccal mucosa cell, oocyte
MCM9	233	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM9	2,092
MCM8	1,952

Intra-cohort edges

A	B	Sources
MCM8	MCM9	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM8	Q9UJA3	7
MCM9	Q9NXL9	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
E2F mediated regulation of DNA replication	1	1631.4×	0.004	MCM8
CDC6 association with the ORC:origin complex	1	1427.5×	0.004	MCM8
E2F-enabled inhibition of pre-replication complex formation	1	1268.9×	0.004	MCM8
DNA strand elongation	1	1142.0×	0.004	MCM8
Unwinding of DNA	1	878.5×	0.005	MCM8
Activation of the pre-replicative complex	1	326.3×	0.007	MCM8
DNA Replication Pre-Initiation	1	317.2×	0.007	MCM8
Activation of ATR in response to replication stress	1	300.5×	0.007	MCM8
Switching of origins to a post-replicative state	1	300.5×	0.007	MCM8
Synthesis of DNA	1	300.5×	0.007	MCM8
DNA Replication	1	237.9×	0.007	MCM8
G1/S Transition	1	233.1×	0.007	MCM8
Mitotic G1 phase and G1/S transition	1	184.2×	0.007	MCM8
S Phase	1	181.3×	0.007	MCM8
Orc1 removal from chromatin	1	178.4×	0.007	MCM8
Assembly of the pre-replicative complex	1	139.3×	0.009	MCM8
G2/M Checkpoints	1	134.3×	0.009	MCM8
Cell Cycle Checkpoints	1	88.5×	0.013	MCM8
Cell Cycle, Mitotic	1	48.2×	0.022	MCM8
Cell Cycle	1	36.0×	0.028	MCM8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
recombinational interstrand cross-link repair	2	8426.0×	3e-08	MCM8, MCM9
mismatch repair involved in maintenance of fidelity involved in DNA-dependent DNA replication	2	8426.0×	3e-08	MCM8, MCM9
female gamete generation	2	802.5×	4e-06	MCM8, MCM9
protein localization to chromatin	2	581.1×	6e-06	MCM8, MCM9
double-strand break repair via homologous recombination	2	156.0×	7e-05	MCM8, MCM9
DNA damage response	2	53.5×	5e-04	MCM8, MCM9
male gamete generation	1	2106.5×	5e-04	MCM8
protein stabilization	1	33.4×	0.030	MCM8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MCM8	0	0
MCM9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MCM8, MCM9

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MCM8	0	—
MCM9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation

Cohort genes: MCM8, MCM9