P3H1

Summary

P3H1 (prolyl 3-hydroxylase 1, HGNC:19316) is a protein-coding gene on chromosome 1p34.2, encoding Prolyl 3-hydroxylase 1 (Q32P28). Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). It is a selective cancer dependency (DepMap: 13.6% of cell lines).

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.

Source: NCBI Gene 64175 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteogenesis imperfecta type 8 (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 990 total — 75 pathogenic, 41 likely-pathogenic
• Phenotypes (HPO): 29
• Cancer dependency (DepMap): dependent in 13.6% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_022356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19316
Approved symbol	P3H1
Name	prolyl 3-hydroxylase 1
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	GROS1, LEPRECAN, MGC117314
Ensembl gene	ENSG00000117385
Ensembl biotype	protein_coding
OMIM	610339
Entrez	64175

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000236040, ENST00000296388, ENST00000372526, ENST00000397054, ENST00000431412, ENST00000447502, ENST00000460031, ENST00000460831, ENST00000462474, ENST00000463465, ENST00000472802, ENST00000481465, ENST00000492956, ENST00000495874, ENST00000907901, ENST00000907902, ENST00000907903, ENST00000907904, ENST00000907905, ENST00000928449, ENST00000928450, ENST00000928451, ENST00000928452, ENST00000964923

RefSeq mRNA: 3 — MANE Select: NM_022356 NM_001146289, NM_001243246, NM_022356

CCDS: CCDS472, CCDS53307, CCDS57986

Canonical transcript exons

ENST00000296388 — 15 exons

Exon	Start	End
ENSE00001080467	42755165	42755217
ENSE00001189735	42754869	42754990
ENSE00001870983	42766507	42767028
ENSE00003482171	42752537	42752664
ENSE00003499862	42747272	42747412
ENSE00003517045	42748200	42748317
ENSE00003538001	42750186	42750336
ENSE00003541057	42755548	42755637
ENSE00003564504	42759201	42759390
ENSE00003574659	42752274	42752369
ENSE00003588309	42758852	42758983
ENSE00003641633	42746374	42746852
ENSE00003671009	42747723	42747798
ENSE00003673287	42757783	42757922
ENSE00003691539	42762323	42762475

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.5928 / max 152.5859, expressed in 1803 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11999	22.5928	1803

Top tissues by expression

274 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.75	gold quality
adenohypophysis	UBERON:0002196	95.07	gold quality
tibial nerve	UBERON:0001323	94.09	gold quality
pituitary gland	UBERON:0000007	93.99	gold quality
tibia	UBERON:0000979	93.95	gold quality
cartilage tissue	UBERON:0002418	93.70	gold quality
right ovary	UBERON:0002118	93.36	gold quality
left ovary	UBERON:0002119	92.92	gold quality
endocervix	UBERON:0000458	92.86	gold quality
ascending aorta	UBERON:0001496	92.62	gold quality
thoracic aorta	UBERON:0001515	92.48	gold quality
body of uterus	UBERON:0009853	92.46	gold quality
granulocyte	CL:0000094	92.41	gold quality
descending thoracic aorta	UBERON:0002345	91.96	gold quality
smooth muscle tissue	UBERON:0001135	91.92	gold quality
left testis	UBERON:0004533	91.87	gold quality
left coronary artery	UBERON:0001626	91.76	gold quality
right adrenal gland cortex	UBERON:0035827	91.73	gold quality
gall bladder	UBERON:0002110	91.70	gold quality
right testis	UBERON:0004534	91.67	gold quality
right lobe of liver	UBERON:0001114	91.64	gold quality
adrenal tissue	UBERON:0018303	91.52	gold quality
right adrenal gland	UBERON:0001233	91.46	gold quality
metanephros cortex	UBERON:0010533	91.29	gold quality
spleen	UBERON:0002106	91.22	gold quality
left uterine tube	UBERON:0001303	91.18	gold quality
aorta	UBERON:0000947	91.16	gold quality
right coronary artery	UBERON:0001625	90.93	gold quality
left adrenal gland cortex	UBERON:0035825	90.82	gold quality
periodontal ligament	UBERON:0008266	90.80	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	15.54
E-ANND-3	yes	10.55
E-GEOD-111727	no	373.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting P3H1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-15B-3P	97.85	66.68	974
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-410-5P	96.55	66.28	459
HSA-MIR-323B-5P	96.12	66.39	472
HSA-MIR-494-5P	95.31	66.29	463
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-6879-3P	93.93	64.00	759

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 13.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• Screening of 78 subjects diagnosed with osteogenesis imperfecta type II or III, identified three probands with mutations in CRTAP and 16 with mutations in LEPRE1. (PMID:18566967)
• Mutations in CRTAP and LEPRE1 are found in 3 patients with type II osteogenesis imperfecta. (PMID:18996919)
• Findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form. (PMID:19088120)
• CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation complex in endoplasmic reticulum. (PMID:19846465)
• Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta. (PMID:19862557)
• We report a large consanguineous Turkish family in which multiple individuals are affected with autosomal recessive lethal or severe osteogenesis imperfecta (OI) due to a novel homozygous LEPRE1 mutation (PMID:20946018)
• Mutation analyses were performed for COL1A1, COL1A2, CRTAP, and LEPRE1 in a cohort of 58 unrelated Chinese patients with osteogenesis imperfecta. (PMID:21667357)
• 0.4% of Mid-Atlantic African Americans and 1.48% West Africans carry mutation in LEPRE1 which causes lethal recessive osteogenesis imperfecta. (PMID:22281939)
• This is the first report of a mutation in LEPRE1 that eliminates only the KDEL ER-retrieval sequence, whereas other functional domains remain intact (PMID:22615817)
• An additional function of the rough endoplasmic reticulum protein complex prolyl 3-hydroxylase 1.cartilage-associated protein.cyclophilin B: the CXXXC motif reveals disulfide isomerase activity in vitro. (PMID:24043621)
• This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI. (PMID:26634552)
• P3H1 mutation is associated with Non-Lethal Type VIII Osteogenesis Imperfecta. (PMID:27383115)
• Osteogenesis imperfecta caused by COL1A1, CRTAP and LEPRE1 mutations. Report of 2cases.", trans “Osteogenesis imperfecta causada por mutacion en los genes COL1A1, CRTAP y LEPRE1. Estudio de 2casos. (PMID:30389107)
• Upregulated LEPRE1 correlates with poor outcome and its knockdown attenuates cells proliferation, migration and invasion in osteosarcoma. (PMID:32197005)
• A new case of osteogenesis imperfecta type VIII and retinal detachment. (PMID:33098264)
• A novel P3H1 mutation is associated with osteogenesis imperfecta type VIII and dental anomalies. (PMID:33737016)
• Osteogenesis Imperfecta: Search for Mutations in Patients from the Republic of Bashkortostan (Russia). (PMID:35052464)
• Biomarker LEPRE1 induces pelitinib-specific drug responsiveness by regulating ABCG2 expression and tumor transition states in human leukemia and lung cancer. (PMID:35190588)
• Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant. (PMID:35327962)
• Cell Surface Accumulation of Intracellular Leucine Proline-Enriched Proteoglycan 1 Enhances Odontogenic Potential of Human Dental Pulp Stem Cells. (PMID:35859453)
• A Founder Intronic Variant in P3H1 Likely Results in Aberrant Splicing and Protein Truncation in Patients of Karen Descent with Osteogenesis Imperfecta Type VIII. (PMID:36833249)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	p3h1	ENSDARG00000071212
mus_musculus	P3h1	ENSMUSG00000028641
rattus_norvegicus	P3h1	ENSRNOG00000053991

Paralogs (2): P3H2 (ENSG00000090530), P3H3 (ENSG00000110811)

Protein

Protein identifiers

Prolyl 3-hydroxylase 1 — Q32P28 (reviewed: Q32P28)

Alternative names: Growth suppressor 1, Leucine- and proline-enriched proteoglycan 1

All UniProt accessions (3): E2QRI1, Q32P28, H7C2W6

UniProt curated annotations — full annotation on UniProt →

Function. Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). Has prolyl 3-hydroxylase activity catalyzing the post-translational formation of 3-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens, especially types IV and V. May be involved in the secretory pathway of cells. Has growth suppressive activity in fibroblasts.

Subcellular location. Endoplasmic reticulum Secreted. Extracellular space. Extracellular matrix.

Post-translational modifications. O-glycosylated; chondroitin sulfate.

Disease relevance. Osteogenesis imperfecta 8 (OI8) [MIM:610915] A form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI8 is characterized by disproportionate short stature, shortening of the long bones, white sclerae, a round face and a short barrel-shaped chest. The disease is caused by variants affecting the gene represented in this entry. A splice site mutation leading to the absence of isoform 1 has been reported in 2 OI8 patients. Isoform 1 is the only form predicted to be located in the endoplasmic reticulum, which the appropriate location for the catalysis of collagen hydroxylation. These patients show indeed severely reduced COL1A1 hydroxylation.

Similarity. Belongs to the leprecan family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q32P28-1	1, GROS1-L, LEPREa, P3H1a	yes
Q32P28-2	2, GROS1-S
Q32P28-3	3, LEPREc
Q32P28-4	4, LEPREb, P3H1b

RefSeq proteins (3): NP_001139761, NP_001230175, NP_071751* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005123	Oxoglu/Fe-dep_dioxygenase_dom	Domain
IPR006620	Pro_4_hyd_alph	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR039575	P3H	Family
IPR044862	Pro_4_hyd_alph_FE2OG_OXY	Domain
IPR056585	Leprecan_dom	Domain

Pfam: PF13640, PF23557

Enzyme classification (BRENDA):

• EC 1.14.11.28 — proline 3-hydroxylase (BRENDA: 5 organisms, 4 substrates, 14 inhibitors, 11 Km, 1 kcat entries)
• EC 1.14.11.7 — procollagen-proline 3-dioxygenase (BRENDA: 5 organisms, 27 substrates, 31 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-PROLINE	0.2–0.56	4
2-OXOGLUTARATE	0.047–0.11	3
L-PIPECOLIC ACID	3.8–100	2
2-OXOGLUTARATE	0.003–0.08	2
3,4-DEHYDRO-L-PROLINE	8.4	1
L-2-AZETIDINECARBOXYLIC ACID	2.1	1
(GLY-L-PRO-L-4-HYDROXYPROLINE)5	0.07	1
L-LEU-L-ASN-GLY-L-LEU-L-4HYP-GLY-L-PRO-L-ILE-GLY	0.26	1
L-PRO-L-THR-GLY-L-PRO-L-ARG-GLY-L-PHE-L-PRO-GLY-	0.07	1
L-SER-L-LYS-GLY-L-GLU-L-GLN-GLY-L-PHE-L-MET-GLY-	0.26	1
O2	0.03	1
PROCOLLAGEN	—	1

Catalyzed reactions (Rhea), 1 shown:

• L-prolyl-[collagen] + 2-oxoglutarate + O2 = trans-3-hydroxy-L-prolyl-[collagen] + succinate + CO2 (RHEA:22872)

UniProt features (79 total): helix 23, strand 19, sequence conflict 6, turn 6, splice variant 4, repeat 4, sequence variant 4, binding site 3, glycosylation site 3, signal peptide 1, chain 1, active site 1, domain 1, region of interest 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8K0M	ELECTRON MICROSCOPY	3.17
8K17	ELECTRON MICROSCOPY	3.18
8K0F	ELECTRON MICROSCOPY	3.37
8K0I	ELECTRON MICROSCOPY	3.62
8K0E	ELECTRON MICROSCOPY	3.65
8KC9	ELECTRON MICROSCOPY	3.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q32P28-F1	86.21	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 669

Ligand- & substrate-binding residues (3): 587; 589; 659

Glycosylation sites (3): 316, 467, 540

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes

MSigDB gene sets: 225 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_BONE_DEVELOPMENT, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, SASAI_RESISTANCE_TO_NEOPLASTIC_TRANSFROMATION, ROZANOV_MMP14_TARGETS_UP, GOBP_PROTEIN_STABILIZATION

GO Biological Process (12): protein folding (GO:0006457), negative regulation of cell population proliferation (GO:0008285), positive regulation of neuron projection development (GO:0010976), protein hydroxylation (GO:0018126), collagen fibril organization (GO:0030199), regulation of ossification (GO:0030278), negative regulation of cell growth (GO:0030308), collagen metabolic process (GO:0032963), regulation of protein secretion (GO:0050708), protein stabilization (GO:0050821), bone development (GO:0060348), negative regulation of post-translational protein modification (GO:1901874)

GO Molecular Function (9): iron ion binding (GO:0005506), procollagen-proline 3-dioxygenase activity (GO:0019797), L-ascorbic acid binding (GO:0031418), protein binding (GO:0005515), collagen binding (GO:0005518), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), membrane (GO:0016020), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), extracellular region (GO:0005576), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Collagen formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
negative regulation of cellular process	2
oxidoreductase activity	2
intracellular membrane-bounded organelle	2
cellular process	1
protein maturation	1
cell population proliferation	1
regulation of cell population proliferation	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
protein modification process	1
extracellular matrix organization	1
ossification	1
regulation of multicellular organismal process	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
metabolic process	1
protein secretion	1
regulation of protein transport	1
regulation of secretion by cell	1
regulation of protein stability	1
skeletal system development	1
animal organ development	1
negative regulation of protein modification process	1
post-translational protein modification	1
regulation of post-translational protein modification	1
transition metal ion binding	1
procollagen-proline dioxygenase activity	1
peptidyl-proline 3-dioxygenase activity	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
binding	1
protein-containing complex binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
P3H1	PPIB	P23284	999
P3H1	CRTAP	O75718	977
P3H1	COL1A2	P02464	890
P3H1	COL1A1	P02452	881
P3H1	SERPINH1	P29043	827
P3H1	FKBP10	Q96AY3	825
P3H1	P4HA2	O15460	810
P3H1	TMEM38B	Q9NVV0	796
P3H1	P4HA1	P13674	766
P3H1	PLOD2	O00469	728
P3H1	IFITM5	A6NNB3	722
P3H1	P4HB	P07237	690
P3H1	SERPINF1	P36955	685
P3H1	TOP3A	Q13472	681
P3H1	RMI1	Q9H9A7	679

IntAct

102 interactions, top by confidence:

A	B	Type	Score
RBM8A	CASC3	psi-mi:“MI:0914”(association)	0.900
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.890
MED26	MED19	psi-mi:“MI:0914”(association)	0.730
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
ZNF397	ZNF213	psi-mi:“MI:0914”(association)	0.640
SF3B4	SF3B1	psi-mi:“MI:0914”(association)	0.610
HRG	PLSCR1	psi-mi:“MI:0914”(association)	0.590
CRTAP	P3H1	psi-mi:“MI:0915”(physical association)	0.560
CDK18	UBL4A	psi-mi:“MI:0914”(association)	0.530
EBNA-LP	HAX1	psi-mi:“MI:0914”(association)	0.530
EDA	AP3B1	psi-mi:“MI:0914”(association)	0.530
INAVA	DCTN6	psi-mi:“MI:0914”(association)	0.530
ZNF397	ZNF197	psi-mi:“MI:0914”(association)	0.530
SNRPN	PRMT5	psi-mi:“MI:0914”(association)	0.530
VPS37D	CRTAP	psi-mi:“MI:0914”(association)	0.530
CSTF2T	CRTAP	psi-mi:“MI:0914”(association)	0.530
ALX3	CRTAP	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
P3H1	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
Sf3a1	U2SURP	psi-mi:“MI:0915”(physical association)	0.400
CPSF3	P4HA2	psi-mi:“MI:0914”(association)	0.350
Smad3		psi-mi:“MI:0914”(association)	0.350
CEP170P1	PCYT1A	psi-mi:“MI:0914”(association)	0.350
Sart3	TARS3	psi-mi:“MI:0914”(association)	0.350
SEC16A	NCOR2	psi-mi:“MI:0914”(association)	0.350
Mtx1	BDP1	psi-mi:“MI:0914”(association)	0.350
KIF21B		psi-mi:“MI:0914”(association)	0.350

BioGRID (241): P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), CRTAP (Co-fractionation), P3H1 (Affinity Capture-MS), P3H1 (Proximity Label-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS), P3H1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMH0, A2ARP1, A5PK74, A7Z050, A9JTG5, B5DE73, B5DFG1, D3YY23, D3ZU57, O00562, O35954, O43304, P0C644, P0CB42, P16386, Q01433, Q02356, Q09200, Q10468, Q32P28, Q3SZL5, Q3U308, Q3V1T4, Q4KLM6, Q5HZW3, Q5RDF1, Q5RF50, Q5U2N3, Q5ZMM1, Q68J42, Q6ICH7, Q6JHU7, Q6PD26, Q6PFW1, Q6YRM6, Q80VP9, Q86TL0, Q8BGV9, Q8BGW1, Q8CG71

Diamond homologs: O75718, Q32P28, Q3V1T4, Q4KLM6, Q64375, Q6JHU7, Q6JHU8, Q8CG71, Q8IVL5, Q8K2B0, Q90830, Q92791, Q9CYD3, Q9R1J8, Q6PK18, Q8CG70, Q8IVL6, Q5M843, Q5XGE0, Q9D136

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 148 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA 3’-end processing	9	16.6×	2e-06
RNA Polymerase II Transcription Termination	8	16.4×	8e-06
Collagen biosynthesis and modifying enzymes	8	12.7×	4e-05
Transport of Mature mRNA derived from an Intron-Containing Transcript	6	8.5×	4e-03
mRNA Splicing	8	8.2×	6e-04
mRNA Polyadenylation	9	7.4×	4e-04
CHD1 and CHD2 subfamily	7	7.1×	3e-03
Processing of Capped Intron-Containing Pre-mRNA	8	6.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
RNA splicing, via transesterification reactions	5	23.8×	6e-04
mRNA splicing, via spliceosome	10	7.0×	6e-04
RNA splicing	9	6.1×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

990 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	75
Likely pathogenic	41
Uncertain significance	315
Likely benign	432
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076376	NM_022356.4(P3H1):c.838C>T (p.Gln280Ter)	Pathogenic
1253	NM_022356.4(P3H1):c.1080+1G>T	Pathogenic
1254	NM_022356.4(P3H1):c.1473+1G>T	Pathogenic
1255	NM_022356.4(P3H1):c.747del (p.Tyr250fs)	Pathogenic
1256	NM_022356.4(P3H1):c.1656C>A (p.Tyr552Ter)	Pathogenic
1257	NM_022356.4(P3H1):c.1365_1366delinsC (p.Glu455fs)	Pathogenic
1258	NM_022356.4(P3H1):c.1102C>T (p.Arg368Ter)	Pathogenic
1332993	NM_022356.4(P3H1):c.1852del (p.Tyr617_Leu618insTer)	Pathogenic
1342297	NM_022356.4(P3H1):c.2051_2054del (p.Glu684fs)	Pathogenic
1361320	NM_022356.4(P3H1):c.2154dup (p.Glu719fs)	Pathogenic
1384126	NM_022356.4(P3H1):c.933C>G (p.Tyr311Ter)	Pathogenic
1390172	NM_022356.4(P3H1):c.2101_2102insT (p.Glu701fs)	Pathogenic
1415316	NM_022356.4(P3H1):c.652G>T (p.Glu218Ter)	Pathogenic
1418473	NM_022356.4(P3H1):c.2055+1G>A	Pathogenic
1431904	NM_022356.4(P3H1):c.765C>A (p.Tyr255Ter)	Pathogenic
1457668	NM_022356.4(P3H1):c.377del (p.Pro126fs)	Pathogenic
1459537	NC_000001.10:g.(?43218172)(43218675_?)del	Pathogenic
1460006	NM_022356.4(P3H1):c.1223+2T>C	Pathogenic
1691307	NM_022356.4(P3H1):c.2143C>T (p.Gln715Ter)	Pathogenic
2002943	NM_022356.4(P3H1):c.1499_1502dup (p.Gly502fs)	Pathogenic
2035332	NM_022356.4(P3H1):c.922C>T (p.Gln308Ter)	Pathogenic
2116019	NM_022356.4(P3H1):c.1658del (p.Phe553fs)	Pathogenic
2166595	NM_022356.4(P3H1):c.438C>A (p.Tyr146Ter)	Pathogenic
2190191	NM_022356.4(P3H1):c.417del (p.Glu139fs)	Pathogenic
2429335	NM_022356.4(P3H1):c.640C>T (p.Arg214Ter)	Pathogenic
2431665	NM_022356.4(P3H1):c.927del (p.Phe309fs)	Pathogenic
2695842	NM_022356.4(P3H1):c.1351_1357del (p.Pro451fs)	Pathogenic
2703233	NM_022356.4(P3H1):c.951T>A (p.Tyr317Ter)	Pathogenic
2710150	NM_022356.4(P3H1):c.791del (p.Leu264fs)	Pathogenic
2722060	NM_022356.4(P3H1):c.898del (p.Leu300fs)	Pathogenic

SpliceAI

2488 predictions. Top by Δscore:

Variant	Effect	Δscore
1:42747271:CCCG:C	donor_gain	1.0000
1:42747409:CTGC:C	acceptor_gain	1.0000
1:42747717:ACTC:A	donor_loss	1.0000
1:42747718:CTCA:C	donor_loss	1.0000
1:42747719:TCACC:T	donor_loss	1.0000
1:42747720:CACC:C	donor_loss	1.0000
1:42747721:A:AC	donor_gain	1.0000
1:42747721:A:T	donor_loss	1.0000
1:42747722:C:CT	donor_gain	1.0000
1:42747722:CCGT:C	donor_gain	1.0000
1:42747794:TGGCG:T	acceptor_gain	1.0000
1:42747795:GGCG:G	acceptor_gain	1.0000
1:42747797:CG:C	acceptor_gain	1.0000
1:42747799:C:CC	acceptor_gain	1.0000
1:42748196:TCAC:T	donor_loss	1.0000
1:42748198:A:AC	donor_gain	1.0000
1:42748198:A:AT	donor_loss	1.0000
1:42748199:C:CT	donor_gain	1.0000
1:42748313:GACCT:G	acceptor_gain	1.0000
1:42748314:ACCT:A	acceptor_gain	1.0000
1:42748315:CCTC:C	acceptor_gain	1.0000
1:42748316:CT:C	acceptor_gain	1.0000
1:42748318:C:CC	acceptor_gain	1.0000
1:42750332:CCCAG:C	acceptor_gain	1.0000
1:42750333:CCAG:C	acceptor_gain	1.0000
1:42750333:CCAGC:C	acceptor_gain	1.0000
1:42750334:CAG:C	acceptor_gain	1.0000
1:42750334:CAGC:C	acceptor_gain	1.0000
1:42750335:AG:A	acceptor_gain	1.0000
1:42750336:GC:G	acceptor_loss	1.0000

AlphaMissense

4798 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:42747302:C:A	W675C	1.000
1:42747302:C:G	W675C	1.000
1:42747304:A:G	W675R	1.000
1:42747304:A:T	W675R	1.000
1:42747352:G:C	H659D	1.000
1:42747374:G:C	F651L	1.000
1:42747374:G:T	F651L	1.000
1:42747375:A:G	F651S	1.000
1:42747376:A:G	F651L	1.000
1:42747300:A:G	F676S	0.999
1:42747306:A:G	L674P	0.999
1:42747309:G:T	A673D	0.999
1:42747318:C:G	C670S	0.999
1:42747319:A:G	C670R	0.999
1:42747319:A:T	C670S	0.999
1:42747322:G:T	R669S	0.999
1:42747336:A:T	V664D	0.999
1:42747356:G:C	N657K	0.999
1:42747356:G:T	N657K	0.999
1:42747375:A:C	F651C	0.999
1:42747750:G:C	F629L	0.999
1:42747750:G:T	F629L	0.999
1:42747751:A:C	F629C	0.999
1:42747751:A:G	F629S	0.999
1:42747752:A:G	F629L	0.999
1:42747771:G:C	F622L	0.999
1:42747771:G:T	F622L	0.999
1:42747773:A:G	F622L	0.999
1:42747788:A:C	Y617D	0.999
1:42747790:A:G	L616P	0.999

dbSNP variants (sampled 300 via entrez): RS1000179810 (1:42753987 G>C), RS1000208421 (1:42767646 A>G), RS1000415288 (1:42749800 C>T), RS1000614178 (1:42748863 C>T), RS1000666480 (1:42748480 A>G), RS1001033744 (1:42768858 G>A), RS1001226352 (1:42754540 A>G), RS1001319945 (1:42761988 C>A), RS1001484415 (1:42763183 A>G), RS1001485054 (1:42768068 G>A), RS1001678897 (1:42754277 G>A), RS1001930545 (1:42763738 T>C), RS1001934293 (1:42767740 A>T), RS1002023717 (1:42749451 T>C), RS1002356116 (1:42763956 T>C)

Disease associations

OMIM: gene MIM:610339 | disease phenotypes: MIM:610915, MIM:259420, MIM:166200, MIM:612955

GenCC curated gene-disease

Disease	Classification	Inheritance
osteogenesis imperfecta type 8	Definitive	Autosomal recessive
osteogenesis imperfecta type 2	Supportive	Autosomal dominant
osteogenesis imperfecta type 3	Supportive	Autosomal dominant

Mondo (5): osteogenesis imperfecta type 8 (MONDO:0012581), osteogenesis imperfecta type 3 (MONDO:0009804), osteogenesis imperfecta (MONDO:0019019), long QT syndrome 12 (MONDO:0013062), osteogenesis imperfecta type 2 (MONDO:0008147)

Orphanet (4): Osteogenesis imperfecta type 3 (Orphanet:216812), Osteogenesis imperfecta (Orphanet:666), Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000260	Wide anterior fontanel
HP:0000311	Round face
HP:0000520	Proptosis
HP:0000703	Dentinogenesis imperfecta
HP:0000883	Thin ribs
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0001263	Global developmental delay
HP:0001382	Joint hypermobility
HP:0001552	Barrel-shaped chest
HP:0002645	Wormian bones
HP:0002650	Scoliosis
HP:0002757	Recurrent fractures
HP:0002808	Kyphosis
HP:0002953	Vertebral compression fracture
HP:0002980	Femoral bowing
HP:0002982	Tibial bowing
HP:0002986	Radial bowing
HP:0003100	Slender long bone
HP:0003784	Type 1 collagen overmodification
HP:0004331	Decreased skull ossification
HP:0005474	Decreased calvarial ossification
HP:0005855	Multiple prenatal fractures
HP:0008796	Femoral retroversion
HP:0008873	Disproportionate short-limb short stature
HP:0010049	Short metacarpal
HP:0011461	Fetal onset

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
C567842	Long Qt Syndrome 12 (supp.)
C536042	Osteogenesis imperfecta, type 2A (supp.)
C536044	Osteogenesis imperfecta, type 3 (supp.)
C536049	Osteogenesis imperfecta, type VIII (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, increases expression	3
sodium arsenite	decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
aflatoxin B2	affects methylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Thiram	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Thapsigargin	increases expression	1
beta-Naphthoflavone	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1LE	Abcam Jurkat P3H1 KO	Cancer cell line	Male
CVCL_D1PH	Abcam K-562 P3H1 KO	Cancer cell line	Female
CVCL_D2L3	Abcam Raji P3H1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

79 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT00001305	PHASE3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	PHASE3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	PHASE3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	PHASE3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	PHASE3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	PHASE3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT05768854	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	PHASE3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT03118570	PHASE2	COMPLETED	A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804
NCT00063479	PHASE2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	PHASE2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	PHASE2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	PHASE2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	PHASE2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	PHASE2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	PHASE2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT05312697	PHASE2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT07062588	PHASE2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	PHASE2	NOT_YET_RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT01061099	PHASE1	COMPLETED	Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta
NCT00705120	PHASE1	COMPLETED	Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
NCT02172885	PHASE1	COMPLETED	Mesenchymal Stem Cell Based Therapy for the Treatment of Osteogenesis Imperfecta
NCT03064074	PHASE1	COMPLETED	Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta
NCT04545554	PHASE1	COMPLETED	Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta
NCT05231668	PHASE1	TERMINATED	Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI)
NCT06086613	PHASE1	COMPLETED	A First-in-Human Study Evaluating AGA2115 in Adult Healthy Volunteers
NCT05559801	PHASE1/PHASE2	NOT_YET_RECRUITING	Mesenchymal Cell Therapy in Osteogenesis Imperfecta (OI)
NCT05125809	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Placebo for Osteogenesis Imperfecta
NCT03706482	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Boost Brittle Bones Before Birth
NCT04623606	PHASE1/PHASE2	UNKNOWN	Boost to Brittle Bones - Stem Cell Transplantation for Treatment of Brittle Bones
NCT00001594	Not specified	COMPLETED	Evaluation and Intervention for the Effects of Osteogenesis Imperfecta
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease