P4HA1

Summary

P4HA1 (prolyl 4-hydroxylase subunit alpha 1, HGNC:8546) is a protein-coding gene on chromosome 10q22.1, encoding Prolyl 4-hydroxylase subunit alpha-1 (P13674). Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.

This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 5033 — RefSeq curated summary.

At a glance

• Gene–disease (curated): connective tissue disorder (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 85 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001017962

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8546
Approved symbol	P4HA1
Name	prolyl 4-hydroxylase subunit alpha 1
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	C-P4Halpha(I)
Ensembl gene	ENSG00000122884
Ensembl biotype	protein_coding
OMIM	176710
Entrez	5033

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 27 protein_coding, 1 retained_intron

ENST00000263556, ENST00000307116, ENST00000373008, ENST00000394890, ENST00000440381, ENST00000464310, ENST00000886200, ENST00000886201, ENST00000886202, ENST00000886203, ENST00000886204, ENST00000886205, ENST00000886206, ENST00000886207, ENST00000886208, ENST00000886209, ENST00000886210, ENST00000924332, ENST00000924333, ENST00000924334, ENST00000951388, ENST00000951389, ENST00000951390, ENST00000951391, ENST00000951392, ENST00000951393, ENST00000951394, ENST00000951395

RefSeq mRNA: 4 — MANE Select: NM_001017962 NM_000917, NM_001017962, NM_001142595, NM_001142596

CCDS: CCDS41537, CCDS44432, CCDS7320

Canonical transcript exons

ENST00000394890 — 15 exons

Exon	Start	End
ENSE00000987124	73068846	73068983
ENSE00001102018	73072029	73072180
ENSE00001102025	73073731	73073827
ENSE00001169944	73009807	73009903
ENSE00001169965	73016846	73016899
ENSE00001169972	73030271	73030370
ENSE00001169991	73051053	73051249
ENSE00001169998	73053351	73053590
ENSE00001170036	73007217	73008292
ENSE00001170044	73074808	73074915
ENSE00003311666	73044981	73045051
ENSE00003440983	73046925	73047101
ENSE00003513888	73014224	73014289
ENSE00003652555	73010969	73011037
ENSE00003998159	73096766	73096866

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 84.0859 / max 1828.8941, expressed in 1822 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110034	82.6991	1822
205900	0.7381	386
205899	0.3197	116
110035	0.2034	44
110032	0.0958	29
110033	0.0297	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	98.82	gold quality
calcaneal tendon	UBERON:0003701	97.66	gold quality
tibia	UBERON:0000979	97.41	gold quality
ventricular zone	UBERON:0003053	97.23	gold quality
pericardium	UBERON:0002407	97.20	gold quality
stromal cell of endometrium	CL:0002255	97.14	gold quality
periodontal ligament	UBERON:0008266	96.92	gold quality
tendon	UBERON:0000043	96.21	gold quality
gastrocnemius	UBERON:0001388	95.93	gold quality
muscle of leg	UBERON:0001383	95.46	gold quality
tibialis anterior	UBERON:0001385	95.19	gold quality
triceps brachii	UBERON:0001509	95.16	gold quality
gluteal muscle	UBERON:0002000	95.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.07	gold quality
adrenal tissue	UBERON:0018303	94.95	gold quality
muscle organ	UBERON:0001630	94.89	gold quality
skeletal muscle organ	UBERON:0014892	94.89	gold quality
biceps brachii	UBERON:0001507	94.76	gold quality
deltoid	UBERON:0001476	94.74	gold quality
heart right ventricle	UBERON:0002080	94.66	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.45	gold quality
skeletal muscle tissue	UBERON:0001134	94.06	gold quality
choroid plexus epithelium	UBERON:0003911	93.95	gold quality
tendon of biceps brachii	UBERON:0008188	93.81	gold quality
endometrium	UBERON:0001295	93.70	gold quality
muscle tissue	UBERON:0002385	93.36	gold quality
caput epididymis	UBERON:0004358	93.24	gold quality
vastus lateralis	UBERON:0001379	92.84	gold quality
smooth muscle tissue	UBERON:0001135	92.77	gold quality
nephron tubule	UBERON:0001231	92.74	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	4059.16
E-MTAB-11121	yes	510.39
E-HCAD-5	yes	31.89
E-CURD-112	yes	15.17
E-HCAD-13	yes	12.43
E-MTAB-9388	yes	11.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, USF1, USF2

miRNA regulators (miRDB)

107 targeting P4HA1, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4679	99.76	69.19	1229

Literature-anchored findings (GeneRIF, showing 33)

• These in vivo data demonstrated that smokers had thinner atherosclerotic cap thickness and lower levels of P4Halpha and collagen. (PMID:15369792)
• Collagen prolyl 4-hydroxylase-alpha (I)mRNA is stabilized by interation of RNA-binding proteins hnRNP-A2/B1 with a U(16) element within the 3’-UTR (PMID:16464861)
• positive (transforming growth factor beta1) and negative (cigarette smoking extract) regulators appear to influence the USF-E-box interaction and affect P4Halpha(I) expression (PMID:16488890)
• Results suggest that the alteration of translational efficiency by nucleolin, which occurs through a hypoxia inducible factor independent pathway, is an important step in collagen prolyl 4-hydroxylase-alpha(I) regulation under hypoxia. (PMID:16837461)
• In comparison with healthy cartilage, Osteoarthritis articular chondrocytes exhibit increased in vivo synthesis of collagen prolyl-4-hydroxylase type II, a pivotal enzyme in collagen triple helix formation. (PMID:16877351)
• HIF-P4H, HIF-1alpha and HIF-2alpha are effective oxygen sensors (PMID:16885164)
• analysis of the 2-His-1-Asp active-site motif in prolyl 4-hydroxylase (PMID:19890397)
• IL-6 significantly downregulated P4Halpha1 expression in aortic smooth muscle cells (PMID:23022409)
• Overexpression of miR-122 markedly attenuated the expression of P4HA1 via targeting a binding site located at 3’-UTR of P4HA1 mRNA (PMID:23178710)
• Studies indicate P4HA1 copy number gain in a subset of metastatic prostate tumors and its expression is also regulated by microRNA-124. (PMID:25115393)
• Thus, we conclude that miR-30e suppresses proliferation of hepatoma cells through targeting P4HA1 mRNA. (PMID:26966067)
• Findings suggest that the catalytic domain of collagen prolyl 4-hydroxylases (CP4Hs) recognizes the cis conformation of the prolyl peptide bond. (PMID:28001367)
• Our study indicates that P4HA1 plays a pivotal role in the process of GSC-EC transdifferentiation and the structural formation of vascular BMs. (PMID:28415787)
• we report compound heterozygous frameshift and splice site mutations in P4HA1 that impair but not abolish C-P4H alpha(I) activity. The maternal P4HA1 exon 12 splice donor site mutation causes an internally deleted C-P4H alpha(I) predicted to completely lack catalytic activity. two nucleic acid insertion in exon 9 results in a premature stop in the exon 9 P4HA1 splice form. (PMID:28419360)
• High expression of P4HA1 was correlated with the malignancy of gliomas and could serve as a prognostic indicator for patients with high-grade gliomas (PMID:28964577)
• miR-122 inhibited migration, invasion, epithelial mesenchymal transition, and metastasis in peritoneal cavity of ovarian cancer cells by targeting P4HA1. (PMID:30136751)
• Collagen prolyl 4-hydroxylase alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived models. Increased P4HA1 expression correlates with short relapse-free survival in TNBC patients who received chemotherapy. (PMID:30367042)
• Findings show that prolyl 4-hydroxylase subunit alpha 1 (P4HA1) can enhance hypoxia-inducible factor 1alpha (HIF1alpha) stability, indicating a positive feedback loop between HIF1alpha and P4HA1 in pancreatic ductal adenocarcinoma (PDAC). (PMID:31239153)
• High P4HA1 expression is an independent prognostic factor for poor overall survival and recurrent-free survival in head and neck squamous cell carcinoma. (PMID:31782831)
• Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls. (PMID:32053263)
• Diagnostic and Prognostic Values of P4HA1 Expression in Lung Cancer, Breast Cancer, and Head and Neck Cancer (PMID:32150689)
• Overexpression of P4HA1 Is Correlated with Poor Survival and Immune Infiltrates in Lung Adenocarcinoma. (PMID:33299876)
• Systematic Analysis of the Expression and Prognostic Significance of P4HA1 in Pancreatic Cancer and Construction of a lncRNA-miRNA-P4HA1 Regulatory Axis. (PMID:33415167)
• Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth. (PMID:34218269)
• Prognostic and diagnostic roles of prolyl 4-hydroxylase subunit alpha members in breast cancer. (PMID:34387118)
• Comprehensive Analysis of Gene Expression Profiles Identifies a P4HA1-Related Gene Panel as a Prognostic Model in Colorectal Cancer Patients. (PMID:34520234)
• Prolyl 4-hydroxylase P4HA1 Mediates the Interplay Between Glucose Metabolism and Stemness in Pancreatic Cancer Cells. (PMID:36043766)
• P4HA1 activates HMGCS1 to promote nasopharyngeal carcinoma ferroptosis resistance and progression. (PMID:36702290)
• P4HA1, transcriptionally activated by STAT1, promotes esophageal cancer progression. (PMID:36734588)
• Identification and verification of FN1, P4HA1 and CREBBP as potential biomarkers in human atrial fibrillation. (PMID:37161136)
• P4HA1 Promotes Cell Migration and Colonization in Hypopharyngeal Squamous Cell Carcinoma. (PMID:37247900)
• Identification and validation of INHBE and P4HA1 as hub genes in non-alcoholic fatty liver disease. (PMID:37922570)
• P4HA1 expression and function in esophageal squamous cell carcinoma. (PMID:38134053)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	p4ha1b	ENSDARG00000071082
mus_musculus	P4ha1	ENSMUSG00000019916
rattus_norvegicus	P4ha1	ENSRNOG00000050655
drosophila_melanogaster	CG31021	FBGN0051021
caenorhabditis_elegans		WBGENE00004026
caenorhabditis_elegans		WBGENE00015773
caenorhabditis_elegans		WBGENE00077688

Paralogs (3): P4HA2 (ENSG00000072682), P4HA3 (ENSG00000149380), P4HTM (ENSG00000178467)

Protein

Protein identifiers

Prolyl 4-hydroxylase subunit alpha-1 — P13674 (reviewed: P13674)

Alternative names: Procollagen-proline,2-oxoglutarate-4-dioxygenase subunit alpha-1

All UniProt accessions (2): P13674, Q5VSQ6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.

Subunit / interactions. Heterotetramer of two alpha-1 chains and two beta chains (P4HB)(the beta chain is the multi-functional PDI), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Expressed in the heart, liver, skeletal muscle, kidney, placenta, lung and pancreas.

Activity regulation. Inhibited by poly(L-proline).

Cofactor. Binds 1 Fe(2+) ion per subunit.

Similarity. Belongs to the P4HA family.

Isoforms (3)

UniProt ID	Names	Canonical?
P13674-1	1	yes
P13674-2	2
P13674-3	3

RefSeq proteins (4): NP_000908, NP_001017962, NP_001136067, NP_001136068 (=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
IPR013547	P4H_N	Domain
IPR019734	TPR_rpt	Repeat
IPR044862	Pro_4_hyd_alph_FE2OG_OXY	Domain
IPR045054	P4HA-like	Family
IPR059068	TPR_P4H	Domain

Pfam: PF08336, PF13640, PF23558

Enzyme classification (BRENDA):

• EC 1.14.11.2 — procollagen-proline 4-dioxygenase (BRENDA: 37 organisms, 182 substrates, 264 inhibitors, 251 Km, 44 kcat entries)

Substrate kinetics (BRENDA)

77 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.001–1	37
POLY(L-PROLINE)	0.0002–1.59	26
(L-PRO-L-PRO-GLY)10	0.015–2.9	15
(PRO-PRO-GLY)10	0.011–1.27	15
POLY(L-PRO)	0.002–0.65	15
FE2+	0.0004–0.016	9
O2	0.03–1.5	9
ASCORBATE	0.14–0.37	8
(L-PRO-L-PRO-GLY)5	0.12–1.8	6
PROTOCOLLAGEN	—	6
(L-PRO-L-ALA-L-PRO-L-LYS)3	0.09–0.31	4
(SER-PRO)5	0.14–0.78	4
DLDLEMLAPYIPMDD	0.009–0.1	3
DLDLEMLAPYIPMDDDF	0.007–0.07	3
EMLAPYIPMDDDFQL	0.007–0.08	3

Catalyzed reactions (Rhea), 1 shown:

• L-prolyl-[collagen] + 2-oxoglutarate + O2 = trans-4-hydroxy-L-prolyl-[collagen] + succinate + CO2 (RHEA:18945)

UniProt features (29 total): helix 12, binding site 4, mutagenesis site 3, splice variant 2, glycosylation site 2, signal peptide 1, chain 1, sequence conflict 1, repeat 1, strand 1, domain 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4BTB	X-RAY DIFFRACTION	1.9
4BT9	X-RAY DIFFRACTION	1.9
2V5F	X-RAY DIFFRACTION	2.03
9HRE	X-RAY DIFFRACTION	2.05
9HT8	X-RAY DIFFRACTION	2.15
9HPQ	X-RAY DIFFRACTION	2.17
4BT8	X-RAY DIFFRACTION	2.2
1TJC	X-RAY DIFFRACTION	2.3
4BTA	X-RAY DIFFRACTION	2.95
2YQ8	X-RAY DIFFRACTION	2.99

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13674-F1	90.23	0.79

Functional residue map

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

Ligand- & substrate-binding residues (4): 429; 431; 500; 510

Glycosylation sites (2): 113, 259

Mutagenesis-validated functional residues (3):

Position	Phenotype
210	strongly reduced affinity for peptide substrate.
213	strongly reduced affinity for peptide substrate.
247	strongly reduced affinity for peptide substrate.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-9918432	Maturation of DENV proteins

MSigDB gene sets: 282 (showing top): WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, ZHAN_LATE_DIFFERENTIATION_GENES_UP, TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, HARRIS_HYPOXIA, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, MAZ_Q6, MENSE_HYPOXIA_UP, AP2_Q3, MODULE_16, GTGCCTT_MIR506, CAGCAGG_MIR370, CADWELL_ATG16L1_TARGETS_DN

GO Biological Process (1): collagen fibril organization (GO:0030199)

GO Molecular Function (9): procollagen-proline 4-dioxygenase activity (GO:0004656), iron ion binding (GO:0005506), L-ascorbic acid binding (GO:0031418), identical protein binding (GO:0042802), protein binding (GO:0005515), 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 (6): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), membrane (GO:0016020), procollagen-proline 4-dioxygenase complex (GO:0016222), collagen trimer (GO:0005581)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Collagen formation	1
Dengue Virus Genome Translation and Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity	2
cytoplasm	2
intracellular membrane-bounded organelle	2
extracellular matrix organization	1
procollagen-proline dioxygenase activity	1
peptidyl-proline 4-dioxygenase activity	1
transition metal ion binding	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
protein binding	1
binding	1
catalytic activity	1
cation binding	1
endomembrane system	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cellular anatomical structure	1
endoplasmic reticulum protein-containing complex	1
oxidoreductase complex	1
protein-containing complex	1

Protein interactions and networks

STRING

2276 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
P4HA1	P4HB	P07237	979
P4HA1	PLOD1	Q02809	871
P4HA1	PLOD2	O00469	824
P4HA1	P3H2	Q8IVL5	779
P4HA1	P3H1	Q32P28	766
P4HA1	EGLN1	Q9GZT9	730
P4HA1	HIF1A	Q16665	708
P4HA1	HIF3A	Q9Y2N7	685
P4HA1	PDIA3	P30101	675
P4HA1	PLOD3	O60568	671
P4HA1	EGLN3	Q9H6Z9	671
P4HA1	PDIA4	P13667	671
P4HA1	COL13A1	Q5TAT6	658
P4HA1	ARNT	P27540	633
P4HA1	AGO4	Q9HCK5	623

IntAct

193 interactions, top by confidence:

A	B	Type	Score
RBM8A	CASC3	psi-mi:“MI:0914”(association)	0.900
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.750
WASL	WIPF3	psi-mi:“MI:0914”(association)	0.740
P4HB	P4HA2	psi-mi:“MI:0914”(association)	0.740
COL1A1	P4HA2	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
PTK2	TGFB1I1	psi-mi:“MI:0914”(association)	0.680
P4HA1	P4HA1	psi-mi:“MI:0407”(direct interaction)	0.650
DNAJC8	SF3B1	psi-mi:“MI:0914”(association)	0.640
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
IRS4	PIK3R2	psi-mi:“MI:0914”(association)	0.640
SF3B4	SF3B1	psi-mi:“MI:0914”(association)	0.610
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
HRG	PLSCR1	psi-mi:“MI:0914”(association)	0.590
P4HA1	P4HA2	psi-mi:“MI:0915”(physical association)	0.560
FOXP3	FOXP2	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
ZNF397	ZNF197	psi-mi:“MI:0914”(association)	0.530
TIGD5	P4HA2	psi-mi:“MI:0914”(association)	0.530
L3MBTL3	P4HA1	psi-mi:“MI:0914”(association)	0.530
COLQ	PLOD3	psi-mi:“MI:0914”(association)	0.530

BioGRID (363): P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), EVPL (Co-fractionation), P4HA1 (Co-fractionation), P4HA1 (Co-fractionation), P4HA1 (Proximity Label-MS), P4HA1 (Proximity Label-MS), P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B5GR44, A0A166YZY4, A7XDQ9, F4HSU3, F4ILF8, F4KF16, O04084, O15460, O23364, P13674, P16924, P43295, P54001, Q0WRX3, Q0WUG6, Q10576, Q16820, Q1PFD9, Q1RMU3, Q4V398, Q5RAG8, Q5UP57, Q5ZLK5, Q60715, Q60716, Q6E279, Q6W3E9, Q84LR6, Q84WF0, Q8GXT7, Q8L7B2, Q8LED3, Q8LPF8, Q8RXQ1, Q8VZJ7, Q8VZU3, Q93ZR8, Q9C7Z9, Q9CAU0, Q9LSV8

Diamond homologs: F4ILF8, F4J0A8, F4JAU3, F4JNU8, F4JZ24, O15460, P0DUB0, P13674, P16924, P54001, Q10576, Q19673, Q1RMU3, Q20065, Q24JN5, Q5RAG8, Q5UP57, Q5ZLK5, Q60715, Q60716, Q6W3E9, Q6W3F0, Q75UG4, Q7Z4N8, Q8BG58, Q8GXT7, Q8L970, Q8LAN3, Q8VZJ7, Q9LN20, Q9NXG6, Q9SZT0, Q9ZW86

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
HIF1A	“up-regulates quantity by expression”	P4HA1	“transcriptional regulation”
P4HA1	“up-regulates quantity by expression”	HMGCS1	“transcriptional regulation”
P4HA1	“up-regulates quantity by expression”	HMGCR	“transcriptional regulation”
P4HA1	“up-regulates quantity”	Collagen	“chemical modification”
P4HA1	“up-regulates activity”	HIF1A
P4HA1	up-regulates	Glycolysis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 201 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 Splicing - Minor Pathway	7	10.9×	3e-04
mRNA Splicing	14	10.7×	2e-08
RNA Polymerase II Transcription Termination	7	10.7×	3e-04
mRNA Polyadenylation	17	10.4×	4e-10
mRNA 3’-end processing	7	9.6×	6e-04
Collagen biosynthesis and modifying enzymes	8	9.5×	2e-04
SARS-CoV-2 modulates host translation machinery	6	9.3×	3e-03
snRNP Assembly	6	8.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	9	32.3×	3e-09
spliceosomal snRNP assembly	7	23.4×	5e-06
peptidyl-tyrosine phosphorylation	8	19.4×	3e-06
vascular endothelial growth factor receptor signaling pathway	5	13.8×	5e-03
mRNA splicing, via spliceosome	19	10.0×	7e-11
cell surface receptor protein tyrosine kinase signaling pathway	10	10.0×	2e-05
protein autophosphorylation	8	6.7×	5e-03
RNA splicing	11	5.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	52
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3024166	NM_001017962.3(P4HA1):c.1148+1030C>T	Likely pathogenic

SpliceAI

2467 predictions. Top by Δscore:

Variant	Effect	Δscore
10:73008288:GGATA:G	acceptor_gain	1.0000
10:73008289:GATA:G	acceptor_gain	1.0000
10:73008289:GATAC:G	acceptor_loss	1.0000
10:73008290:ATAC:A	acceptor_loss	1.0000
10:73008291:TA:T	acceptor_gain	1.0000
10:73008291:TACT:T	acceptor_loss	1.0000
10:73008292:ACTG:A	acceptor_loss	1.0000
10:73008293:C:CC	acceptor_gain	1.0000
10:73008293:C:CG	acceptor_loss	1.0000
10:73008294:T:A	acceptor_loss	1.0000
10:73010963:GCTTA:G	donor_loss	1.0000
10:73010964:CTTAC:C	donor_loss	1.0000
10:73010965:TTA:T	donor_loss	1.0000
10:73010966:TACT:T	donor_loss	1.0000
10:73010967:A:AC	donor_gain	1.0000
10:73010967:A:T	donor_loss	1.0000
10:73010968:C:CC	donor_gain	1.0000
10:73010968:CT:C	donor_gain	1.0000
10:73010968:CTT:C	donor_gain	1.0000
10:73010968:CTTT:C	donor_gain	1.0000
10:73010968:CTTTT:C	donor_gain	1.0000
10:73011033:CTCAT:C	acceptor_gain	1.0000
10:73011034:TCAT:T	acceptor_gain	1.0000
10:73011035:CAT:C	acceptor_gain	1.0000
10:73011035:CATC:C	acceptor_gain	1.0000
10:73011036:ATCT:A	acceptor_loss	1.0000
10:73011037:TCTAT:T	acceptor_loss	1.0000
10:73011038:C:CC	acceptor_gain	1.0000
10:73011038:C:CG	acceptor_loss	1.0000
10:73013185:CATG:C	donor_gain	1.0000

AlphaMissense

3508 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:73014245:T:A	R449S	1.000
10:73014245:T:G	R449S	1.000
10:73008279:C:A	W516C	0.999
10:73008279:C:G	W516C	0.999
10:73008281:A:G	W516R	0.999
10:73008281:A:T	W516R	0.999
10:73009808:C:A	W511C	0.999
10:73009808:C:G	W511C	0.999
10:73009810:A:G	W511R	0.999
10:73009810:A:T	W511R	0.999
10:73009811:T:A	K510N	0.999
10:73009811:T:G	K510N	0.999
10:73009832:A:C	C503W	0.999
10:73009833:C:T	C503Y	0.999
10:73009834:A:G	C503R	0.999
10:73009843:G:C	H500D	0.999
10:73009878:A:G	L488P	0.999
10:73009880:A:C	N487K	0.999
10:73009880:A:T	N487K	0.999
10:73009886:C:A	W485C	0.999
10:73009886:C:G	W485C	0.999
10:73009888:A:G	W485R	0.999
10:73009888:A:T	W485R	0.999
10:73009896:G:T	A482D	0.999
10:73011002:A:C	F468L	0.999
10:73011002:A:T	F468L	0.999
10:73011003:A:C	F468C	0.999
10:73011003:A:G	F468S	0.999
10:73011004:A:G	F468L	0.999
10:73014240:G:T	A451D	0.999

dbSNP variants (sampled 300 via entrez): RS1000021879 (10:73097663 A>C), RS1000052993 (10:73097197 T>C), RS1000056416 (10:73059181 T>C), RS1000080456 (10:73021320 A>G), RS1000112418 (10:73013270 T>C), RS1000115429 (10:73053376 C>A,T), RS1000142494 (10:73072858 A>G), RS1000184791 (10:73055025 G>A), RS1000198341 (10:73072430 T>C), RS1000210352 (10:73040516 G>A), RS1000215167 (10:73091356 G>A), RS1000264702 (10:73027300 G>C,T), RS1000297046 (10:73079934 T>C), RS1000347442 (10:73033681 A>C), RS1000368861 (10:73078904 G>A)

Disease associations

OMIM: gene MIM:176710 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
connective tissue disorder	Limited	Autosomal recessive

Mondo (1): connective tissue disorder (MONDO:0003900)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90011898_75	Alanine aminotransferase levels	2.000000e-09

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1250350 (SINGLE PROTEIN)

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 10 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.88	Kd	0.132	nM	CHEMBL5653589
9.88	ED50	0.132	nM	CHEMBL5653589
6.85	Ki	140	nM	CHEMBL332005
6.70	Ki	200	nM	CHEMBL3586252
6.29	Kd	510.8	nM	CHEMBL3752910
6.29	ED50	510.8	nM	CHEMBL3752910
6.08	IC50	840	nM	CHEMBL332005
5.92	IC50	1200	nM	CHEMBL3586252
5.58	Ki	2600	nM	PYRIDINE-2,5-DICARBOXYLIC ACID

PubChem BioAssay actives

7 with measured affinity, of 20 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148923: Binding affinity to human P4HA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0001	uM
6-(5-carboxy-2-pyridinyl)pyridine-3-carboxylic acid	1230196: Inhibition of human human recombinant CP4H1 expressed in Escherichia coli Origami B(DE3) pre-incubated for 2 mins followed by alpha-ketoglutarate addition using dansylGlyProProGlyOEt substrate in Tris-HCl buffer at pH 7.8 at 30 degC by HPLC based Cheng-Prussoff equation method	ki	0.1400	uM
6-(4-carboxy-2-pyridinyl)pyridine-3-carboxylic acid	1230196: Inhibition of human human recombinant CP4H1 expressed in Escherichia coli Origami B(DE3) pre-incubated for 2 mins followed by alpha-ketoglutarate addition using dansylGlyProProGlyOEt substrate in Tris-HCl buffer at pH 7.8 at 30 degC by HPLC based Cheng-Prussoff equation method	ki	0.2000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148923: Binding affinity to human P4HA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.5108	uM
pyridine-2,5-dicarboxylic acid	1230196: Inhibition of human human recombinant CP4H1 expressed in Escherichia coli Origami B(DE3) pre-incubated for 2 mins followed by alpha-ketoglutarate addition using dansylGlyProProGlyOEt substrate in Tris-HCl buffer at pH 7.8 at 30 degC by HPLC based Cheng-Prussoff equation method	ki	2.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Oxygen	increases reaction, increases expression, affects binding	6
bisphenol A	affects expression, decreases expression, increases expression	4
Valproic Acid	decreases methylation, affects expression, decreases expression	4
Cyclosporine	decreases expression	3
Cadmium Chloride	increases expression, decreases reaction, increases abundance, increases palmitoylation	3
methylmercuric chloride	decreases expression	2
sodium arsenite	decreases expression, affects expression	2
cobaltous chloride	increases expression, decreases reaction	2
Tetrachlorodibenzodioxin	decreases expression	2
Aflatoxin B1	affects expression, increases methylation	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
selenomethylselenocysteine	increases expression	1
2,4,6-tribromophenol	increases expression	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
diethyl phthalate	decreases expression, increases abundance	1
decabromobiphenyl ether	increases expression	1
ferric ammonium citrate	decreases reaction, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
zinc chloride	decreases reaction, increases expression	1
tetrabromobisphenol A	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
nickel chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	increases abundance, increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1243628	Binding	Activity of collagen prolyl 4 hydroxylase-1	Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one? — Nat Chem Biol

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease
NCT00341679	Not specified	COMPLETED	Studies of the Natural History and Pathogenesis of Autoimmune/Connective Tissue Diseases
NCT00470327	Not specified	RECRUITING	A Study of the Natural Progression of Interstitial Lung Disease (ILD)
NCT00491309	Not specified	UNKNOWN	Exercise and Respiratory Therapy in Patients With Rheumatoid Arthritis / Collagenosis and Pulmonary Hypertension