ZP4

Chr 1

zona pellucida glycoprotein 4

Also known as: ZBP, ZP1, ZP1B, ZPB, ZPB2, Zp-4

NCBI Gene: 57829ENSG00000116996UniProt: Q12836

The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a consensus furin cleavage site, and a C-terminal transmembrane domain. It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix. However, the requirement for furin cleavage in this process remains controversial based on mouse studies. Previously, this gene has been referred to as ZP1 or ZPB and thought to have similar functions as mouse Zp1. However, a human gene with higher similarity and chromosomal synteny to mouse Zp1 has been assigned the symbol ZP1 and this gene has been assigned the symbol ZP4. [provided by RefSeq, Jul 2008]

154
ClinVar variants
48
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ZP4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
48 Pathogenic / Likely Pathogenic· 89 VUS of 154 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.31LOEUF
pLI 0.000
Z-score 0.21
OE 0.96 (0.71–1.31)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.24Z-score
OE missense 1.20 (1.10–1.31)
357 obs / 296.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.96 (0.71–1.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.20 (1.10–1.31)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.19
0≤1.21.6
LoF obs/exp: 28 / 29.2Missense obs/exp: 357 / 296.8Syn Z: -1.60

ClinVar Variant Classifications

154 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic1
VUS89
Likely Benign13
Benign4
47
Pathogenic
1
Likely Pathogenic
89
VUS
13
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
47
0
47
Likely Pathogenic
0
0
1
0
1
VUS
0
81
8
0
89
Likely Benign
0
11
0
2
13
Benign
0
4
0
0
4
Total096562154

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ZP4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mutations in ZP4 are associated with abnormal zona pellucida and female infertility.
Wei X et al.·J Clin Pathol
2022
Study on the zona pellucida 4 (ZP4) gene sequence and its expression in the ovaries of patients with polycystic ovary syndrome.
Meczekalski B et al.·J Endocrinol Invest
2015Cohort
Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review.
Zhou J et al.·Reprod Biol Endocrinol
2022Review
Novel mutation in the ZP1 gene and clinical implications.
Yuan P et al.·J Assist Reprod Genet
2019
Effect of In Vitro Maturation of Human Oocytes Obtained After Controlled Ovarian Hormonal Stimulation on the Expression of Development- and Zona Pellucida-Related Genes and Their Interactions.
Bedenk J et al.·Reprod Sci
2023
Novel zona pellucida gene variants identified in patients with oocyte anomalies.
Yang P et al.·Fertil Steril
2017Cohort
Characterization of human sperm binding to homologous recombinant zona pellucida proteins.
Chirinos M et al.·Reprod Sci
2011
Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putative stem cells in adult mammalian ovary.
Parte S et al.·Stem Cells Dev
2011
A single domain of the ZP2 zona pellucida protein mediates gamete recognition in mice and humans.
Avella MA et al.·J Cell Biol
2014
The effect of preparation height and luting agent on the resistance form of cemented cast crowns under load fatigue.
Leong EW et al.·J Prosthet Dent
2009
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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External Resources

Links to major genomics databases and tools