Female infertility due to zona pellucida defect

Summary

Female infertility due to zona pellucida defect (MONDO:0014342) is a disease caused by ZP1 (GenCC Strong), with 4 cohort genes. The dominant Reactome pathway is Interaction With Cumulus Cells And The Zona Pellucida (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ZP1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	female infertility due to zona pellucida defect
Mondo ID	MONDO:0014342
OMIM	615774
Orphanet	404466
UMLS	C4014291
MedGen	862728
GARD	0017675
Is cancer (heuristic)	no

Also known as: oocyte maturation defect · OOMD · OOMD1

Data availability: 15 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 oocyte maturation defect › female infertility due to zona pellucida defect

Related subtypes (23): oocyte maturation defect 5, oocyte maturation defect 2, oocyte maturation defect 3, oocyte maturation defect 4, oocyte maturation defect 11, oocyte maturation defect 12, oocyte maturation defect 10, oocyte maturation defect 6, oocyte maturation defect 7, oocyte maturation defect 8, oocyte maturation defect 9, oocyte maturation defect 13, oocyte maturation defect 14, oocyte/zygote/embryo maturation arrest 17, oocyte/zygote/embryo maturation arrest 18, oocyte/zygote/embryo maturation arrest 19, oocyte/zygote/embryo maturation arrest 20, oocyte/zygote/embryo maturation arrest 21, oocyte/zygote/embryo maturation arrest 22, oocyte/zygote/embryo maturation arrest 23, oocyte/zygote/embryo maturation arrest 24, oocyte/zygote/embryo maturation arrest 25, oocyte/zygote/embryo maturation arrest 16

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

15 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172840	NM_001372179.1(PABPC1L):c.1037C>T (p.Ala346Val)	PABPC1L	Pathogenic	no assertion criteria provided
127200	NM_207341.4(ZP1):c.1169_1176del (p.Ile390fs)	ZP1	Pathogenic	no assertion criteria provided
3353935	NM_207341.4(ZP1):c.670C>T (p.Arg224Ter)	ZP1	Pathogenic	criteria provided, single submitter
3382275	NM_207341.4(ZP1):c.1129_1130del (p.Val377fs)	ZP1	Pathogenic	criteria provided, single submitter
3382920	NM_207341.4(ZP1):c.1113-2A>G	ZP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3383023	NM_207341.4(ZP1):c.1602C>A (p.Cys534Ter)	ZP1	Pathogenic	criteria provided, single submitter
3780815	NM_207341.4(ZP1):c.874C>T (p.Gln292Ter)	ZP1	Pathogenic	criteria provided, single submitter
689404	NM_207341.4(ZP1):c.1708G>A (p.Val570Met)	ZP1	Pathogenic	criteria provided, single submitter
689405	NM_207341.4(ZP1):c.1430+1G>T	ZP1	Pathogenic	no assertion criteria provided
689406	NM_207341.4(ZP1):c.1775-8T>C	ZP1	Pathogenic	no assertion criteria provided
812693	NM_207341.4(ZP1):c.1168del (p.Ile390fs)	ZP1	Pathogenic	criteria provided, single submitter
1709476	NM_207341.4(ZP1):c.1378G>A (p.Ala460Thr)	ZP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438696	NM_207341.4(ZP1):c.72G>A (p.Leu24=)	ZP1	Uncertain significance	criteria provided, single submitter
3823493	NM_207341.4(ZP1):c.1322G>A (p.Arg441Gln)	ZP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4796544	NM_207341.4(ZP1):c.1588A>G (p.Ser530Gly)	ZP1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 3 · 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
ZP2	Definitive	Autosomal recessive	oocyte maturation defect 6	5
ZP1	Strong	Autosomal recessive	female infertility due to zona pellucida defect	5
ZP3	Strong	Autosomal dominant	oocyte maturation defect 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZP1	Orphanet:404466	Female infertility due to zona pellucida defect
ZP2	Orphanet:404466	Female infertility due to zona pellucida defect
ZP3	Orphanet:404466	Female infertility due to zona pellucida defect

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZP1	HGNC:13187	ENSG00000149506	P60852	Zona pellucida sperm-binding protein 1	gencc,clinvar
ZP2	HGNC:13188	ENSG00000103310	Q05996	Zona pellucida sperm-binding protein 2	gencc
ZP3	HGNC:13189	ENSG00000188372	P21754	Zona pellucida sperm-binding protein 3	gencc
PABPC1L	HGNC:15797	ENSG00000101104	Q4VXU2	Polyadenylate-binding protein 1-like	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZP1	Zona pellucida sperm-binding protein 1	Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy.
ZP2	Zona pellucida sperm-binding protein 2	Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy.
ZP3	Zona pellucida sperm-binding protein 3	Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy.
PABPC1L	Polyadenylate-binding protein 1-like	Poly(A)-binding protein involved in oocyte maturation and early embryo development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Antibody/Immunoglobulin	1	7.3×	0.260
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZP1	Antibody/Immunoglobulin	yes		P_trefoil_dom, ZP_dom, P_trefoil_CS
ZP2	Other/Unknown	no		ZP_dom, ZP_dom_CS, ZP-C_dom
ZP3	Other/Unknown	no		ZP_dom, ZP_dom_CS, ZP-C_dom
PABPC1L	Other/Unknown	no		RRM_dom, PABP_HYD_C, RRM_euk-type

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
oocyte	1
secondary oocyte	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
lower esophagus mucosa	1
primordial germ cell in gonad	1
body of pancreas	1
left lobe of thyroid gland	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZP1	143	tissue_specific	yes	oocyte, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte
ZP2	63	tissue_specific	yes	cerebellar cortex, cerebellum, cerebellar hemisphere
ZP3	134	ubiquitous	marker	lower esophagus mucosa, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
PABPC1L	210	ubiquitous	yes	body of pancreas, right lobe of liver, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PABPC1L	1,729
ZP2	1,426
ZP1	1,139
ZP3	805

Intra-cohort edges

A	B	Sources
ZP1	ZP2	intact, string_interaction
ZP1	ZP3	intact, string_interaction
ZP2	ZP3	intact, string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZP2	Q05996	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZP3	P21754	77.32
PABPC1L	Q4VXU2	76.41
ZP1	P60852	73.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction With Cumulus Cells And The Zona Pellucida	3	1038.2×	1e-09	ZP1, ZP2, ZP3
M-decay: degradation of maternal mRNAs by maternally stored factors	1	108.8×	0.009	ZP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
binding of sperm to zona pellucida	3	316.0×	1e-06	ZP1, ZP2, ZP3
prevention of polyspermy	2	1404.3×	7e-06	ZP1, ZP2
positive regulation of type IV hypersensitivity	1	4213.0×	0.001	ZP3
egg coat formation	1	4213.0×	0.001	ZP3
positive regulation of antral ovarian follicle growth	1	4213.0×	0.001	ZP3
positive regulation of acrosomal vesicle exocytosis	1	2106.5×	0.001	ZP3
positive regulation of ovarian follicle development	1	2106.5×	0.001	ZP3
positive regulation of humoral immune response	1	1053.2×	0.002	ZP3
negative regulation of binding of sperm to zona pellucida	1	1053.2×	0.002	ZP3
humoral immune response mediated by circulating immunoglobulin	1	842.6×	0.003	ZP3
positive regulation of acrosome reaction	1	383.0×	0.005	ZP3
positive regulation of leukocyte migration	1	247.8×	0.007	ZP3
oocyte development	1	234.1×	0.007	ZP3
blastocyst formation	1	191.5×	0.008	ZP3
oocyte maturation	1	150.5×	0.010	PABPC1L
positive regulation of interleukin-4 production	1	140.4×	0.010	ZP3
positive regulation of T cell proliferation	1	64.8×	0.020	ZP3
positive regulation of translation	1	56.9×	0.020	PABPC1L
positive regulation of type II interferon production	1	56.2×	0.020	ZP3
positive regulation of inflammatory response	1	36.3×	0.030	ZP3
negative regulation of DNA-templated transcription	1	7.9×	0.127	ZP3
positive regulation of DNA-templated transcription	1	7.0×	0.136	ZP3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZP1	0	0
ZP2	0	0
ZP3	0	0
PABPC1L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ZP1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	ZP1
E	Difficult family or no structure, no drug	3	ZP2, ZP3, PABPC1L

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZP1	1	—
ZP2	0	—
ZP3	0	—
PABPC1L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.