P3H1

Chr 1AR

prolyl 3-hydroxylase 1

Also known as: GROS1, LEPRE1, OI8

NCBI Gene: 64175ENSG00000117385UniProt: Q32P28

This gene encodes an enzyme that is a member of the collagen prolyl hydroxylase family. These enzymes are localized to the endoplasmic reticulum and their activity is required for proper collagen synthesis and assembly. Mutations in this gene are associated with osteogenesis imperfecta type VIII. Three alternatively spliced transcript variants encoding different isoforms have been described. Other variants may exist, but their biological validity has not been determined. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

Osteogenesis imperfecta, type VIIIMIM #610915
AR
1024
ClinVar variants
87
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— P3H1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
87 Pathogenic / Likely Pathogenic· 122 VUS of 1024 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.
1.23LOEUF
pLI 0.000
Z-score 0.48
OE 0.91 (0.69–1.23)
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.
0.75Z-score
OE missense 0.90 (0.83–0.98)
410 obs / 455.3 exp
Tolerant

Mild missense constraint

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.0.91 (0.69–1.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.83–0.98)
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.0.95
0≤1.21.6
LoF obs/exp: 32 / 35.1Missense obs/exp: 410 / 455.3Syn Z: 0.53

ClinVar Variant Classifications

1024 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52
Likely Pathogenic35
VUS122
Likely Benign258
Benign21
Conflicting2
52
Pathogenic
35
Likely Pathogenic
122
VUS
258
Likely Benign
21
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
33
0
19
0
52
Likely Pathogenic
25
2
8
0
35
VUS
1
114
6
1
122
Likely Benign
0
7
105
146
258
Benign
0
1
20
0
21
Conflicting
—2
Total59124158147490

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

View in ClinVar →

Protein Context — Lollipop Plot

P3H1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

P3H1-related osteogenesis imperfecta

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Osteogenesis imperfecta, type VIII

MIM #610915

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant.
Zhytnik L et al.·Genes (Basel)
2022Cohort
A Founder Intronic Variant in P3H1 Likely Results in Aberrant Splicing and Protein Truncation in Patients of Karen Descent with Osteogenesis Imperfecta Type VIII.
Kantaputra PN et al.·Genes (Basel)
2023Cohort
Genotype and Phenotype Correlation of Patients with Osteogenesis Imperfecta.
Aliyeva L et al.·J Mol Diagn
2024Cohort
Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1-further expansion of the phenotypic spectrum.
Mikhail KA et al.·Cold Spring Harb Mol Case Stud
2023
Pan-Cancer Analysis of P3H1 and Experimental Validation in Renal Clear Cell Carcinoma.
Li Y et al.·Appl Biochem Biotechnol
2024
A novel P3H1 mutation is associated with osteogenesis imperfecta type VIII and dental anomalies.
Kantaputra PN et al.·Oral Surg Oral Med Oral Pathol Oral Radiol
2021
Expanding the Genotypic and Phenotypic Spectrum of P3H1 Related Osteogenesis Imperfecta.
Kındış E et al.·Calcif Tissue Int
2025
Molecular and Clinical Landscape of Osteogenesis Imperfecta: Unraveling Autosomal Recessive Forms, Therapeutic Outcomes, and Bone Mineral Density in Carriers.
Sait H et al.·Clin Genet
2025
Clinical, genetic characteristics and treatment outcomes of children and adolescents with osteogenesis imperfecta: a two-center experience.
Erbaş İM et al.·Connect Tissue Res
2022
Severe cases of osteogenesis imperfecta type VIII due to a homozygous mutation in P3H1 (LEPRE1) and review of the literature.
Bala MM et al.·Adv Clin Exp Med
2021Case report
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.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools