Premature ovarian failure 3

Summary

Premature ovarian failure 3 (MONDO:0012169) is a disease with 2 cohort genes and 2 clinical trials.

At a glance

• Cohort genes: 2
• ClinVar variants: 20
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	premature ovarian failure 3
Mondo ID	MONDO:0012169
MeSH	C563816
OMIM	608996
DOID	DOID:0080860
UMLS	C1837008
MedGen	373230
GARD	0024851
Is cancer (heuristic)	no

Also known as: Pof3 · premature ovarian failure 3 · premature ovarian failure type 3

Data availability: 20 ClinVar variants · 1 GenCC gene-disease record.

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 3

Related subtypes (40): blepharophimosis, ptosis, and epicanthus inversus syndrome, congenital lipoid adrenal hyperplasia due to STAR deficency, ataxia telangiectasia, classic galactosemia, 46 XX gonadal dysgenesis, premature ovarian failure 2A, premature ovarian failure 2B, premature ovarian failure 1, Satoyoshi syndrome, osteosclerosis-ichthyosis-premature ovarian failure syndrome, premature ovarian failure 5, premature ovarian failure 6, premature ovarian failure 7, aromatase deficiency, premature ovarian failure 8, premature ovarian failure 9, 46,XX ovarian dysgenesis-short stature syndrome, premature ovarian failure 11, premature ovarian failure 12, Perrault syndrome, trisomy X, Turner syndrome, tetrasomy X, X small rings, premature ovarian failure 17, premature ovarian failure 18, premature ovarian failure 20, premature ovarian failure 19, premature ovarian failure 16, premature ovarian failure 13, premature ovarian failure 10, premature ovarian failure 14, premature ovarian failure 15, premature ovarian failure 4, premature ovarian failure 21, premature ovarian failure 22, premature ovarian failure 23, premature ovarian failure 24, premature ovarian failure 25, premature ovarian failure 26

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

20 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 7 pathogenic, 3 conflicting classifications of pathogenicity, 2 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162045	NM_023067.4(FOXL2):c.843_859dup (p.Pro287fs)	FOXL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709921	NM_023067.4(FOXL2):c.871del (p.His291fs)	FOXL2	Pathogenic	criteria provided, single submitter
4853	NM_023067.4(FOXL2):c.655C>T (p.Gln219Ter)	FOXL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4858	NM_023067.4(FOXL2):c.804dup (p.Gly269fs)	FOXL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4861	NM_023067.4(FOXL2):c.822C>G (p.Tyr274Ter)	FOXL2	Pathogenic	criteria provided, single submitter
4862	NM_023067.3(FOXL2):c.684684AGCTGCGGCTGCAGC[3] (p.Ala234_Gly235insAlaAlaAlaAlaAlaAlaAlaAlaAlaAla)	FOXL2	Pathogenic	criteria provided, single submitter
503493	NM_023067.4(FOXL2):c.988dup (p.Ala330fs)	FOXL2	Pathogenic	no assertion criteria provided
522614	NM_023067.4(FOXL2):c.462_468del (p.Pro156fs)	FOXL2	Pathogenic	no assertion criteria provided
2577022	NM_012154.5(AGO2):c.2479G>T (p.Gly827Ter)	AGO2	Likely pathogenic	criteria provided, single submitter
134454	NM_023067.4(FOXL2):c.1045C>G (p.Arg349Gly)	FOXL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381980	NM_023067.4(FOXL2):c.335T>G (p.Phe112Cys)	FOXL2	Likely pathogenic	criteria provided, single submitter
3382396	NM_023067.4(FOXL2):c.695_696insTGCAGCCGCAGCGGCTGCAGCAGCTGCGGCTGC (p.Ala234_Gly235insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla)	FOXL2	Likely pathogenic	criteria provided, single submitter
3382461	NM_023067.4(FOXL2):c.9del (p.Ser4fs)	FOXL2	Likely pathogenic	criteria provided, single submitter
3588612	NM_023067.4(FOXL2):c.594del (p.Phe199fs)	FOXL2	Likely pathogenic	criteria provided, single submitter
4868	NM_023067.4(FOXL2):c.663_692del (p.Ala225_Ala234del)	FOXL2	Likely pathogenic	criteria provided, single submitter
1318744	NM_023067.4(FOXL2):c.672_674del (p.Ala234del)	FOXL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4869	NM_023067.4(FOXL2):c.772T>A (p.Tyr258Asn)	FOXL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4871	NM_023067.4(FOXL2):c.560G>A (p.Gly187Asp)	FOXL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2255892	NM_023067.4(FOXL2):c.211G>C (p.Ala71Pro)	FOXL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
369900	NM_023067.4(FOXL2):c.308G>A (p.Arg103His)	FOXL2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
FOXL2	Limited	Unknown	premature ovarian failure 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXL2	Orphanet:572333	Blepharophimosis-ptosis-epicanthus inversus syndrome plus
FOXL2	Orphanet:572354	Blepharophimosis-ptosis-epicanthus inversus syndrome type 1
FOXL2	Orphanet:572361	Blepharophimosis-ptosis-epicanthus inversus syndrome type 2
FOXL2	Orphanet:99915	Malignant granulosa cell tumor of the ovary
AGO2	Orphanet:528084	Non-specific syndromic intellectual disability

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
FOXL2	HGNC:1092	ENSG00000183770	P58012	Forkhead box protein L2	gencc,clinvar
AGO2	HGNC:3263	ENSG00000123908	Q9UKV8	Protein argonaute-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXL2	Forkhead box protein L2	Transcriptional regulator.
AGO2	Protein argonaute-2	Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXL2	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
AGO2	Other/Unknown	no		PAZ_dom, Piwi, RNaseH-like_sf

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
left ovary	1
ovary	1
stromal cell of endometrium	1
cartilage tissue	1
cauda epididymis	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXL2	84	broad	marker	left ovary, stromal cell of endometrium, ovary
AGO2	279	ubiquitous	marker	colonic epithelium, cartilage tissue, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGO2	7,108
FOXL2	1,727

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AGO2	Q9UKV8	67
FOXL2	P58012	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 63. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of NPAS4 gene expression	1	951.7×	0.012	AGO2
Post-transcriptional silencing by small RNAs	1	815.7×	0.012	AGO2
Competing endogenous RNAs (ceRNAs) regulate PTEN translation	1	713.8×	0.012	AGO2
Regulation of CDH11 mRNA translation by microRNAs	1	634.4×	0.012	AGO2
Regulation of NPAS4 mRNA translation	1	634.4×	0.012	AGO2
Regulation of PD-L1(CD274) translation	1	634.4×	0.012	AGO2
Small interfering RNA (siRNA) biogenesis	1	571.0×	0.012	AGO2
Regulation of PTEN mRNA translation	1	571.0×	0.012	AGO2
Regulation of CDH1 mRNA translation by microRNAs	1	519.1×	0.012	AGO2
Regulation of CDH11 Expression and Function	1	407.9×	0.012	AGO2
Transcriptional regulation of testis differentiation	1	356.9×	0.012	FOXL2
Maternal to zygotic transition (MZT)	1	356.9×	0.012	AGO2
Regulation of RUNX1 Expression and Activity	1	335.9×	0.012	AGO2
Regulation of Homotypic Cell-Cell Adhesion	1	335.9×	0.012	AGO2
Regulation of Expression and Function of Type II Classical Cadherins	1	335.9×	0.012	AGO2
Regulation of MITF-M-dependent genes involved in apoptosis	1	317.2×	0.012	AGO2
SUMOylation of transcription factors	1	285.5×	0.012	FOXL2
Transcriptional Regulation by NPAS4	1	285.5×	0.012	AGO2
MicroRNA (miRNA) biogenesis	1	228.4×	0.014	AGO2
TGFBR3 expression	1	228.4×	0.014	AGO2
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.014	AGO2
Pre-NOTCH Expression and Processing	1	184.2×	0.014	AGO2
Regulation of MECP2 expression and activity	1	184.2×	0.014	AGO2
Signaling by TGFBR3	1	184.2×	0.014	AGO2
Gene Silencing by RNA	1	178.4×	0.014	AGO2
Nuclear events stimulated by ALK signaling in cancer	1	163.1×	0.014	AGO2
M-decay: degradation of maternal mRNAs by maternally stored factors	1	163.1×	0.014	AGO2
Transcriptional Regulation by MECP2	1	158.6×	0.014	AGO2
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.014	AGO2
Beta-catenin independent WNT signaling	1	146.4×	0.014	AGO2

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
female somatic sex determination	1	8426.0×	0.002	FOXL2
granulosa cell differentiation	1	8426.0×	0.002	FOXL2
siRNA-mediated gene silencing by mRNA destabilization	1	8426.0×	0.002	AGO2
oocyte growth	1	2106.5×	0.003	FOXL2
positive regulation of luteinizing hormone secretion	1	1685.2×	0.003	FOXL2
RNA stabilization	1	1685.2×	0.003	AGO2
extraocular skeletal muscle development	1	1404.3×	0.003	FOXL2
miRNA-mediated gene silencing by mRNA destabilization	1	1404.3×	0.003	AGO2
positive regulation of follicle-stimulating hormone secretion	1	1404.3×	0.003	FOXL2
positive regulation of trophoblast cell migration	1	1203.7×	0.003	AGO2
negative regulation of amyloid precursor protein biosynthetic process	1	1053.2×	0.004	AGO2
siRNA processing	1	936.2×	0.004	AGO2
embryonic eye morphogenesis	1	766.0×	0.004	FOXL2
RISC complex assembly	1	766.0×	0.004	AGO2
miRNA metabolic process	1	702.2×	0.004	AGO2
positive regulation of nuclear-transcribed mRNA poly(A) tail shortening	1	648.1×	0.004	AGO2
apoptotic DNA fragmentation	1	601.9×	0.004	FOXL2
regulatory ncRNA-mediated post-transcriptional gene silencing	1	601.9×	0.004	AGO2
pre-miRNA processing	1	561.7×	0.004	AGO2
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	561.7×	0.004	AGO2
P-body assembly	1	526.6×	0.004	AGO2
miRNA processing	1	526.6×	0.004	AGO2
regulation of synapse maturation	1	468.1×	0.004	AGO2
miRNA-mediated gene silencing by inhibition of translation	1	443.5×	0.004	AGO2
negative regulation of translational initiation	1	443.5×	0.004	AGO2
uterus development	1	401.2×	0.004	FOXL2
regulatory ncRNA-mediated gene silencing	1	337.0×	0.005	AGO2
ovarian follicle development	1	195.9×	0.007	FOXL2
positive regulation of translation	1	113.9×	0.012	AGO2
post-embryonic development	1	102.8×	0.013	AGO2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
AGO2	SULFANILAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AGO2	4	4
FOXL2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SULFANILAMIDE	4	AGO2
SULFAGUANIDINE	4	AGO2
SULFISOMIDINE	4	AGO2
SURAMIN	3	AGO2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AGO2	6	Binding:6

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

4 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.

Compound	Max phase	Cohort target (bioactivity)
SULFANILAMIDE	4	AGO2
SULFAGUANIDINE	4	AGO2
SULFISOMIDINE	4	AGO2
SURAMIN	3	AGO2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AGO2
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	1	FOXL2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials