P4HA1

protein-coding

prolyl 4-hydroxylase subunit alpha 1

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:

P4HA

MANE transcript

NM_001017962.3

Inheritance

ClinVar variants

P:1U:63B:9

Top phenotype

P4HA1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr10:73,007,217-73,096,974

External References & Databases

Ensembl (ENSG00000122884)

Transcript & Mutation Effects

hg38 • Region Span ~89.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

connective tissue disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0003900

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to P4HA1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 49

P4HA1-related disorderTotal: 14

not providedTotal: 4

Congenital disorder of connective tissueTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001017962.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	6 clinvar	1 clinvar	9
missense			56 clinvar	1 clinvar	1 clinvar	58
nonsense		1 clinvar				1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	63	7	2	73

Highest pathogenic variant AF is 0.000015499782

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 79 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001017962.3	RefSeq	NP_001017962.1	14	MANE Select
ENST00000394890.7	Ensembl	ENSP00000378353.2	14	MANE Select
NM_000917.4	RefSeq	NP_000908.2	14	Standard
NM_001142595.2	RefSeq	NP_001136067.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Collagen biosynthesis and modifying enzymes
Collagen formation
Extracellular matrix organization
Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine

Biological Process

peptidyl-proline hydroxylation to 4-hydroxy-L-proline
collagen fibril organization
oxidation-reduction process

Molecular Function

procollagen-proline 4-dioxygenase activity
iron ion binding
protein binding
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen
L-ascorbic acid binding

Cellular Component

mitochondrion
endoplasmic reticulum
endoplasmic reticulum lumen
membrane
procollagen-proline 4-dioxygenase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000412021
Coding exons: 14
Length: 89758
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125743
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.01	195	292	0.668	0.0000154	3500
Missense (PolyPhen)		52	125.02	0.41592		1494
Synonymous	0.407	96	101	0.949	0.00000513	994
Loss of Function	4.29	5	30.6	0.163	0.00000138	385

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

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

Recessive Scores

pRec: 0.345

Intolerance Scores

LoFtool: 0.745
RVIS EVS: -0.29
RVIS percentile EVS: 32.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.988

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium