PRODH2

protein-coding

proline dehydrogenase 2

Gene summary

The protein encoded by this gene catalyzes the first step in the catabolism of trans-4-hydroxy-L-proline, an amino acid derivative obtained through food intake and collagen turnover. One of the downstream products of this catabolism is glyoxylate, which in people with disorders of glyoxalate metabolism can lead to an increase in oxalate levels and the formation of calcium-oxalate kidney stones. Therefore, this gene may serve as a therapeutic target against primary hyperoxalurias (PH). This gene is similar to proline dehydrogenase (oxidase) 1, a mitochondrial enzyme that catalyzes the first step in proline catabolism. [provided by RefSeq, Jan 2017]

MANE transcript

NM_021232.2

Inheritance

ClinVar variants

U:96B:11

Top phenotype

Hyperhydroxyprolinemia

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr19:35,799,988-35,813,299

External References & Databases

Ensembl (ENSG00000250799)

Transcript & Mutation Effects

hg38 • Region Span ~13.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hydroxyprolinemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009374

Submitter: PanelApp Australia

hydroxyprolinemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009374

Submitter: ClinGen

The relationship between *PRODH2* and hydroxyprolinemia, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 21st, 2019. Hydroxyprolinemia is a benign condition. Most individuals are identified by newborn screening because the mass spectra of hydroxyproline, isoleucine and leucine cannot be differentiated, resulting in false positive screening results for maple syrup urine disease in individuals with hydroxyprolinemia. *PRODH2* encodes hydroxyproline dehydrogenase, which converts hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate. Biallelic variants in PRODH2 causing hydroxyprolinemia were first reported by Staufner et al in 2016 (PMID 27139199); this is currently the only available publication reporting variants in *PRODH2* in individuals with hydroxyprolinemia. Data from 5 patients who are homozygous or compound heterozygous for *PRODH2* variants were curated, including 7 unique variants (missense, nonsense, inframe deletion). Of note, an individual with a heterozygous missense variant in *PRODH2* and a very mildly elevated hydroxyproline level was also reported. However, further studies are required to determine whether heterozygous variants in this gene are consistently associated with hydroxyprolinemia. An individual with hydroxyprolinemia and no identified *PRODH2* variants was also reported, suggesting that other genes may also be involved. However, biochemical evidence is consistent with a defect in *PRODH2.* This gene-disease relationship is supported by the biochemical function of hydroxyproline dehydrogenase, which is consistent with the elevation of hydroxyproline observed in affected individuals (Carnie et al, 1982, PMID 7083820). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. It was reevaluated on 10/14/2022 with one added article citing a knock out mouse model and again on 12/16/2025 with no new evidence identified. As a result of this reevaluation, the classification remained Limited.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRODH2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 93

HyperhydroxyprolinemiaTotal: 7

not providedTotal: 4

PRODH2-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021232.2. 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			1 clinvar	1 clinvar	2 clinvar	4
missense			94 clinvar	7 clinvar	1 clinvar	102
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	96	8	3	107

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021232.2	RefSeq	NP_067055.2	10	MANE Select
ENST00000653904.2	Ensembl	ENSP00000499779.1	10	MANE Select
NM_001378292.1	RefSeq	NP_001365221.1	9	Standard
NM_001378293.1	RefSeq	NP_001365222.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Proline catabolism
Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism
Metabolism of amino acids and derivatives
Metabolism

Biological Process

proline catabolic process
proline catabolic process to glutamate
glyoxylate metabolic process
oxidation-reduction process

Molecular Function

proline dehydrogenase activity
oxidoreductase activity, acting on the CH-NH group of donors
FAD binding

Cellular Component

mitochondrion
mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301175
Coding exons: 11
Length: 13312
Individuals with no LoFs: 125441
Homozygous LoFs: 1
Heterozygous LoFs: 305
Defined: 125747
p: 0.00122

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.118	314	320	0.981	0.0000204	3348
Missense (PolyPhen)		85	101.71	0.83573		1064
Synonymous	0.205	136	139	0.978	0.00000862	1178
Loss of Function	0.798	22	26.4	0.832	0.00000148	269

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.0019	0.0019	notable
Finnish	0.0062	0.0062	notable
European (Non-Finnish)	0.00088	0.00087	rare
South Asian	0.00027	0.00026	rare
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Dehydrogenase that converts trans-4-L-hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate (Hyp) using ubiquinone- 10 as the terminal electron acceptor. Can also use proline as a substrate but with a very much lower efficiency. Does not react with other diastereomers of Hyp: trans-4-D-hydroxyproline and cis- 4-L-hydroxyproline. Ubiquininone analogs such as menadione, duroquinone and ubiquinone-1 react more efficiently than oxygen as the terminal electron acceptor during catalysis. {ECO:0000269|PubMed:25697095}.;

Intolerance Scores

LoFtool: 0.930
RVIS EVS: 0.27
RVIS percentile EVS: 70.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.219

Gene Damage Prediction

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