PRODH

Summary

PRODH (proline dehydrogenase 1, HGNC:9453) is a protein-coding gene on chromosome 22q11.21, encoding Proline dehydrogenase 1, mitochondrial (O43272). Converts proline to delta-1-pyrroline-5-carboxylate.

This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5625 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperprolinemia type 1 (Definitive, ClinGen)
• GWAS associations: 28
• Clinical variants (ClinVar): 490 total — 16 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 22
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_016335

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9453
Approved symbol	PRODH
Name	proline dehydrogenase 1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	HSPOX2, PRODH1, PIG6, PRODH2, TP53I6, POX
Ensembl gene	ENSG00000100033
Ensembl biotype	protein_coding
OMIM	606810
Entrez	5625

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 8 retained_intron

ENST00000313755, ENST00000334029, ENST00000357068, ENST00000399694, ENST00000420436, ENST00000429300, ENST00000438924, ENST00000446371, ENST00000450579, ENST00000457083, ENST00000482858, ENST00000491604, ENST00000496625, ENST00000609229, ENST00000610940, ENST00000881001, ENST00000881002, ENST00000881003, ENST00000881004, ENST00000881005, ENST00000916124, ENST00000916125, ENST00000916126, ENST00000965627, ENST00000965628, ENST00000965629

RefSeq mRNA: 3 — MANE Select: NM_016335 NM_001195226, NM_001368250, NM_016335

CCDS: CCDS13754, CCDS56223

Canonical transcript exons

ENST00000357068 — 14 exons

Exon	Start	End
ENSE00001833573	18936015	18936293
ENSE00003465975	18925051	18925200
ENSE00003471678	18918316	18918491
ENSE00003478205	18912781	18913362
ENSE00003488051	18916890	18916988
ENSE00003493343	18930990	18931198
ENSE00003501304	18919451	18919597
ENSE00003558751	18923115	18923179
ENSE00003593423	18921342	18921423
ENSE00003609682	18925688	18925722
ENSE00003609835	18919706	18919798
ENSE00003610071	18922325	18922404
ENSE00003635228	18913438	18913526
ENSE00003659586	18922817	18922933

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 94.15.

FANTOM5 (CAGE): breadth broad, TPM avg 5.9381 / max 379.1181, expressed in 560 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193122	5.9381	560

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	94.15	gold quality
zone of skin	UBERON:0000014	93.78	gold quality
skin of abdomen	UBERON:0001416	93.33	gold quality
tibial nerve	UBERON:0001323	92.86	gold quality
amygdala	UBERON:0001876	92.72	gold quality
temporal lobe	UBERON:0001871	92.69	gold quality
caudate nucleus	UBERON:0001873	92.30	gold quality
right lung	UBERON:0002167	92.08	gold quality
nucleus accumbens	UBERON:0001882	91.85	gold quality
putamen	UBERON:0001874	91.59	gold quality
apex of heart	UBERON:0002098	91.52	gold quality
sural nerve	UBERON:0015488	90.49	gold quality
duodenum	UBERON:0002114	90.47	gold quality
right frontal lobe	UBERON:0002810	89.88	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.53	gold quality
gastrocnemius	UBERON:0001388	89.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.92	gold quality
Ammon’s horn	UBERON:0001954	88.57	gold quality
small intestine	UBERON:0002108	88.39	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.03	gold quality
anterior cingulate cortex	UBERON:0009835	88.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.42	gold quality
metanephros cortex	UBERON:0010533	87.30	gold quality
primary visual cortex	UBERON:0002436	87.14	gold quality
substantia nigra	UBERON:0002038	86.79	gold quality
muscle of leg	UBERON:0001383	86.74	gold quality
skeletal muscle organ	UBERON:0014892	86.65	gold quality
upper lobe of left lung	UBERON:0008952	86.44	gold quality
hypothalamus	UBERON:0001898	85.20	gold quality
brain	UBERON:0000955	85.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	10.93
E-HCAD-25	yes	4.25
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2, KDM5B, MYC, PPARG, TP53, TP63, TP73

miRNA regulators (miRDB)

25 targeting PRODH, 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-10401-5P	99.99	65.79	948
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-647	97.73	67.79	927
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-4486	96.96	60.61	931
HSA-MIR-6724-5P	96.41	63.11	507
HSA-MIR-151A-5P	95.79	68.73	162
HSA-MIR-151B	95.79	68.73	162

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Proline oxidase induces apoptosis in tumor cells (PMID:12514185)
• A complete homozygous PRODH deletion has been identified in a child with type I hyperprolinemia with severe neurological manifestations. (PMID:12525555)
• Genetic analysis of PRODH reveals no association with schizophrenia. (PMID:12815738)
• Finding supports a role for the PRODH locus in schizophrenia. (PMID:15274030)
• Results suggest that the molecular basis for increased plasma proline levels in schizophrenic subjects carrying the missense mutation Leu441Pro is due to decreased stability of human PRODH2. (PMID:15449943)
• No association was found between common PRODH polymorphisms and any of the psychotic disorders. Five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. (PMID:15494707)
• severe hyperprolinemia (>800 microM) occurs in individuals with large deletions and/or PRODH missense mutations (PMID:15662599)
• proline oxidase mediates apoptosis through the generation of proline-dependent ROS, which then mobilize calcium and activate calcineurin (PMID:15914462)
• induction of apoptosis by troglitazone may, at least in part, be mediated by targeting POX gene expression for generation of ROS by POX both by PPARgamma-dependent and -independent mechanisms (PMID:16303758)
• proline oxidase may modulate apoptosis signals induced by p53 or other anti-cancer agents and enhance apoptosis in stress situations (PMID:16619034)
• this meta-analysis did not find statistically significant evidence for association between RGS4 and PRODH and schizophrenia on the basis of either allelic or genotypic analysis. (PMID:16791139)
• In the presence of proline, high POX activity is sufficient to induce mitochondria-mediated apoptosis. (PMID:16874462)
• Analysis of the PRODH gene coding sequence variations,predicted that POX residual activity results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia. (PMID:17135275)
• Patients with biallelic PRODH alterations resulting in severely impaired proline oxidase activity had an early onset and severe neurological features. (PMID:17412540)
• we found evidence for COMT and PRODH epistasis: in patients with a COMT Val allele (rs4680) and with one or two mutated PRODH alleles, we observed increased WM density in the left inferior frontal lobe. (PMID:17504246)
• Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing. (PMID:17604122)
• In conjunction with the chromosomal location of PRODH, study findings suggest a potential involvement of this gene in the 22q11-associated cognitive, psychiatric and behavioral phenotypes. (PMID:18163391)
• Four Italian children with Type I hyperprolinemia presenting epilepsy, mental retardation, and behavioral disorders for PRODH gene mutations were screened, and a genotype-phenotype correlation was attempted. (PMID:18197084)
• Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers (PMID:18794809)
• A family-based sample showed functional polymorphisms in POX are associated with schizophrenia, with protective and risk alleles having opposite effects on POX activity. (PMID:18989458)
• Kinetic studies of the structural determinants of PRODH substrate specificity focus on how the enzyme discriminates between two closely related molecules, proline and hydroxyproline. (PMID:19140736)
• We assessed the relationship between these high-risk PRODH polymorphisms and schizophrenia-related endophenotypes (PMID:19232576)
• Glucose deprivation increased intracellular proline levels, and expression of POX activated the pentose phosphate pathway. (PMID:19415679)
• POX is a mitochondrial tumor suppressor and a potential target for cancer therapy. (PMID:19654292)
• POX is critical in the cellular response to the noxious effects of oxLDL by activating protective autophagy. (PMID:19942609)
• miR-23b, by targeting proline oxidase, could function as an oncogene. (PMID:20562915)
• For a number of genes affected by de novo copy number variants CNVs in autism (CNTNAP2, ZNF214, ARID1B, Proline Dehydrogenase), reduced transcript expression may be a mechanism of pathogenesis during neurodevelopment. (PMID:21448237)
• There is no association between proline dehydrogenase (oxidase) 1 polymorphisms and schizophrenia in Korean population (PMID:21960278)
• The findings from this study showed that troglitazone-induced apoptosis was mediated by POX-induced ROS formation, at least partly, via PPARgamma activation. (PMID:22108328)
• results provide evidence that PRODH is essential in proline protection against hydrogen peroxide-mediated cell death and that proline/PRODH helps activate Akt in cancer cells (PMID:22796327)
• distinct molecular alterations of the PRODH gene result in abnormal proline levels. (PMID:23462603)
• PRODH, but not PRODH2, expression is under the control of p53 family members, specifically p53 and p73. (PMID:23861960)
• The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating. (PMID:23910792)
• Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH. (PMID:24218577)
• Data indicate that a functional proline dehydrogenase (PRODH) variant associated with schizophrenia that may have a neurochemical impact, altering brain function, but is not responsible for the cortical reductions found in the disorder. (PMID:24498354)
• Functional COMT, but not PRODH, variant affects IQ and executive functions in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood (PMID:24853458)
• results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS (PMID:25325218)
• Thirty-five percent of the subjects were hyperprolinemic, allele carriers of PRODH rs450046 had a lower full-scale intelligence compared to T allele carriers (PMID:26068888)
• GR and KLF15 physically interact via low affinity GR binding sites within glucocorticoid response elements (GREs) for PRODH and AASS that contribute to combinatorial regulation with KLF15. (PMID:26088140)
• The findings support a major role for the PRODH 757TT, 1766GG, and 1852AA genotypes alone and in combination for schizophrenia susceptibility. (PMID:26436492)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	prodhb	ENSDARG00000086512
danio_rerio	prodha	ENSDARG00000086746
mus_musculus	Prodh	ENSMUSG00000003526
rattus_norvegicus	Prodh	ENSRNOG00000000281
drosophila_melanogaster	slgA	FBGN0003423
caenorhabditis_elegans		WBGENE00007197

Paralogs (2): PRODH2 (ENSG00000250799), (ENSG00000277196)

Protein

Protein identifiers

Proline dehydrogenase 1, mitochondrial — O43272 (reviewed: O43272)

Alternative names: Proline oxidase, Proline oxidase 2, p53-induced gene 6 protein

All UniProt accessions (5): O43272, C9JIW4, E7EQL6, H7C363, H7C3U9

UniProt curated annotations — full annotation on UniProt →

Function. Converts proline to delta-1-pyrroline-5-carboxylate.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Expressed in lung, skeletal muscle and brain, to a lesser extent in heart and kidney, and weakly in liver, placenta and pancreas.

Disease relevance. Hyperprolinemia 1 (HYRPRO1) [MIM:239500] An inborn error of proline metabolism resulting in elevated levels of proline in the plasma and urine. The disorder is generally benign and most affected individuals are clinically asymptomatic. Some patients, however, have neurologic manifestations, including epilepsy and intellectual disability. Association with certain forms of schizophrenia have been reported. The disease is caused by variants affecting the gene represented in this entry. Schizophrenia 4 (SCZD4) [MIM:600850] A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Induction. During p53/TP53-induced apoptosis.

Pathway. Amino-acid degradation; L-proline degradation into L-glutamate; L-glutamate from L-proline: step 1/2.

Similarity. Belongs to the proline oxidase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43272-4	1	yes
O43272-2	2
O43272-1	3

RefSeq proteins (3): NP_001182155, NP_001355179, NP_057419* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002872	Proline_DH_dom	Domain
IPR015659	Proline_oxidase	Family
IPR029041	FAD-linked_oxidoreductase-like	Homologous_superfamily

Pfam: PF01619

Enzyme classification (BRENDA):

• EC 1.5.5.2 — proline dehydrogenase (BRENDA: 15 organisms, 30 substrates, 25 inhibitors, 33 Km, 23 kcat entries)
• EC 1.5.99.B2 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-PROLINE	0.0166–340	23
TRANS-4-HYDROXY-L-PROLINE	190–750	3
NAD+	0.0235–42	2
2,6-DICHLOROPHENOLINDOPHENOL	0.0034	1

Catalyzed reactions (Rhea), 1 shown:

• L-proline + a quinone = (S)-1-pyrroline-5-carboxylate + a quinol + H(+) (RHEA:23784)

UniProt features (36 total): sequence variant 20, sequence conflict 8, splice variant 3, modified residue 2, transit peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43272-F1	85.29	0.62

Functional residue map

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

Post-translational modifications (2): 368, 486

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-70688	Proline catabolism

MSigDB gene sets: 239 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GNF2_HPN, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, SMID_BREAST_CANCER_RELAPSE_IN_LUNG_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, HNF1_Q6, LEE_LIVER_CANCER_CIPROFIBRATE_DN, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, RICKMAN_METASTASIS_DN, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS

GO Biological Process (6): L-proline metabolic process (GO:0006560), L-proline catabolic process (GO:0006562), intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0008631), obsolete L-proline catabolic process to L-glutamate (GO:0010133), trans-4-hydroxy-L-proline catabolic process (GO:0019470), regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway (GO:1903376)

GO Molecular Function (4): proline dehydrogenase activity (GO:0004657), oxidoreductase activity, acting on the CH-NH group of donors, quinone or similar compound as acceptor (GO:0016649), FAD binding (GO:0071949), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-amino acid catabolic process	2
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
L-proline metabolic process	1
proteinogenic amino acid catabolic process	1
intrinsic apoptotic signaling pathway	1
modified amino acid catabolic process	1
non-proteinogenic amino acid catabolic process	1
neuron intrinsic apoptotic signaling pathway in response to oxidative stress	1
regulation of neuron apoptotic process	1
regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1
oxidoreductase activity, acting on the CH-NH group of donors, quinone or similar compound as acceptor	1
oxidoreductase activity, acting on the CH-NH group of donors	1
flavin adenine dinucleotide binding	1
catalytic activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRODH	ALDH4A1	P30038	983
PRODH	ALDH4A1	P30038	981
PRODH	COMT	P21964	894
PRODH	DGCR6	Q14129	890
PRODH	COMT	P21964	890
PRODH	DGCR6L	Q9BY27	884
PRODH	ALDH18A1	P54886	861
PRODH	ALDH18A1	P54886	859
PRODH	OAT	P04181	846
PRODH	OAT	P04181	844
PRODH	ZDHHC8	Q9ULC8	837
PRODH	ZDHHC8	Q9ULC8	824
PRODH	GNB1L	Q9BYB4	807
PRODH	DGCR6L	Q9BY27	796
PRODH	DGCR6	Q14129	796

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SLC23A3	PRODH	psi-mi:“MI:0915”(physical association)	0.400
PRODH	TUSC2	psi-mi:“MI:0915”(physical association)	0.400
PRODH	HSPA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): CAPN11 (Co-fractionation), PRODH (Affinity Capture-MS), BRAP (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), HSPA6 (Affinity Capture-MS), HSPA2 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), PRODH (Negative Genetic), TST (Negative Genetic), PRODH (Negative Genetic), PRODH (Negative Genetic), PRODH (Positive Genetic), HSPA2 (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA8 (Affinity Capture-MS)

ESM2 similar proteins: A1A4I4, A4K436, A6QLH6, D3ZVM4, F1M5F3, F1N2W9, O00459, O08908, O43272, O60336, O95294, P0C928, P23726, P70268, Q0VGM9, Q16512, Q1JQD7, Q1PSW8, Q3KRC5, Q496Y0, Q5M9F8, Q5R812, Q5RE34, Q5RJZ1, Q5RKZ7, Q5XIS9, Q5ZIW1, Q63433, Q63788, Q6H1L8, Q6NS57, Q6NYU2, Q6PFQ7, Q8BZ03, Q8R1T1, Q91XI1, Q920N2, Q92889, Q92994, Q96G46

Diamond homologs: A6QQ74, O43272, O45228, P09368, Q04499, Q148G5, Q2V057, Q6PAY6, Q8VCZ9, Q9UF12, Q9WU79, O74524, Q6NKX1, Q86H28, Q9XB58, P92983

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MYC	“down-regulates quantity by repression”	PRODH	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	8
Uncertain significance	207
Likely benign	133
Benign	82

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1179113	GRCh37/hg19 22q11.21(chr22:18900294-18923806)	Pathogenic
1399310	NM_016335.6(PRODH):c.236T>A (p.Leu79Ter)	Pathogenic
1425627	NM_016335.6(PRODH):c.522_526dup (p.Lys176fs)	Pathogenic
1457425	NC_000022.10:g.(?18910310)(18923800_?)del	Pathogenic
1974075	NM_016335.6(PRODH):c.543C>A (p.Tyr181Ter)	Pathogenic
1998253	NM_016335.6(PRODH):c.969_972del (p.Ser323fs)	Pathogenic
2021179	NM_016335.6(PRODH):c.323del (p.Leu108fs)	Pathogenic
2134144	NM_016335.6(PRODH):c.379C>T (p.Gln127Ter)	Pathogenic
2166769	NM_016335.6(PRODH):c.38dup (p.Cys13fs)	Pathogenic
2167860	NM_016335.6(PRODH):c.457del (p.Glu153fs)	Pathogenic
2682549	NC_000022.10:g.(?18900293)(18923807_?)del	Pathogenic
3247249	NC_000022.10:g.(?18900688)(18923800_?)del	Pathogenic
3708754	NM_016335.6(PRODH):c.1094del (p.Val365fs)	Pathogenic
4012	NM_016335.6(PRODH):c.1561C>G (p.Arg521Gly)	Pathogenic
521785	NM_016335.6(PRODH):c.1236C>A (p.Tyr412Ter)	Pathogenic
625620	GRCh37/hg19 22q11.21(chr22:18918741-20311922)	Pathogenic
1179165	GRCh37/hg19 22q11.21(chr22:18900895-18923882)	Likely pathogenic
2201654	NM_016335.6(PRODH):c.1104+2T>C	Likely pathogenic
3587798	NM_016335.6(PRODH):c.1252-1G>A	Likely pathogenic
3587800	NM_016335.6(PRODH):c.1251+2C>T	Likely pathogenic
3587804	NM_016335.6(PRODH):c.1177_1183del (p.Leu393fs)	Likely pathogenic
3587838	NM_016335.6(PRODH):c.148_157del (p.Val50fs)	Likely pathogenic
3587846	NM_016335.6(PRODH):c.2T>G (p.Met1Arg)	Likely pathogenic
3587847	NM_016335.6(PRODH):c.1A>C (p.Met1Leu)	Likely pathogenic

SpliceAI

2794 predictions. Top by Δscore:

Variant	Effect	Δscore
22:18913358:CTGGC:C	acceptor_gain	1.0000
22:18913359:TGGC:T	acceptor_gain	1.0000
22:18913363:C:CC	acceptor_gain	1.0000
22:18916885:CCTA:C	donor_loss	1.0000
22:18916886:CTA:C	donor_loss	1.0000
22:18916887:TACCT:T	donor_loss	1.0000
22:18916889:C:A	donor_loss	1.0000
22:18916989:C:CG	acceptor_loss	1.0000
22:18916990:T:A	acceptor_loss	1.0000
22:18918314:ACCT:A	donor_loss	1.0000
22:18918315:CC:C	donor_loss	1.0000
22:18918488:CATC:C	acceptor_gain	1.0000
22:18919489:TCTCC:T	donor_gain	1.0000
22:18919504:T:TA	donor_gain	1.0000
22:18919594:CTTT:C	acceptor_gain	1.0000
22:18919595:TTT:T	acceptor_gain	1.0000
22:18919595:TTTCT:T	acceptor_loss	1.0000
22:18919596:TT:T	acceptor_gain	1.0000
22:18919596:TTCT:T	acceptor_loss	1.0000
22:18919597:TCTGA:T	acceptor_loss	1.0000
22:18919598:C:CC	acceptor_gain	1.0000
22:18919606:C:CT	acceptor_gain	1.0000
22:18919608:C:CT	acceptor_gain	1.0000
22:18919609:A:T	acceptor_gain	1.0000
22:18919700:GCTCA:G	donor_loss	1.0000
22:18919701:CTCAC:C	donor_loss	1.0000
22:18919702:TCA:T	donor_loss	1.0000
22:18919703:CA:C	donor_loss	1.0000
22:18919705:C:A	donor_loss	1.0000
22:18919795:CTGT:C	acceptor_gain	1.0000

AlphaMissense

3899 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000761903 (22:18926204 C>T), RS1000896487 (22:18917471 G>C), RS1001369870 (22:18936471 GC>G), RS1001975894 (22:18937488 G>A), RS1002301791 (22:18914649 C>A), RS1002551601 (22:18923859 A>G), RS1003528730 (22:18938354 C>A), RS1004292580 (22:18917001 C>T), RS1004598441 (22:18925929 A>G), RS1004680078 (22:18929279 C>A,T), RS1004835533 (22:18921133 G>A), RS1004880277 (22:18936132 G>A,C), RS1004911486 (22:18935979 C>T), RS1005325893 (22:18917986 G>A), RS1005801776 (22:18937130 C>T)

Disease associations

OMIM: gene MIM:606810 | disease phenotypes: MIM:239500, MIM:600850, MIM:188400

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperprolinemia type 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hyperprolinemia type 1	Definitive	AR

Mondo (3): hyperprolinemia type 1 (MONDO:0009400), schizophrenia 4 (MONDO:0010943), DiGeorge syndrome (MONDO:0008564)

Orphanet (2): Hyperprolinemia type 1 (Orphanet:419), 22q11.2 deletion syndrome (Orphanet:567)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000112	Nephropathy
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0002133	Status epilepticus
HP:0002353	EEG abnormality
HP:0003080	Hydroxyprolinuria
HP:0003108	Hyperglycinuria
HP:0003137	Prolinuria
HP:0008358	Hyperprolinemia
HP:0100753	Schizophrenia

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST001217_28	Metabolic traits	2.000000e-22
GCST005648_32	Serum metabolite concentrations in chronic kidney disease	2.000000e-17
GCST007382_1	Plasma free amino acid levels (adjusted for twenty other PFAAs)	7.000000e-11
GCST007382_2	Plasma free amino acid levels (adjusted for twenty other PFAAs)	7.000000e-11
GCST007382_23	Plasma free amino acid levels (adjusted for twenty other PFAAs)	1.000000e-69
GCST007383_1	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-14
GCST007383_10	Plasma free amino acid levels (adjusted for one other PFAA)	5.000000e-09
GCST007383_19	Plasma free amino acid levels (adjusted for one other PFAA)	6.000000e-07
GCST007383_2	Plasma free amino acid levels (adjusted for one other PFAA)	7.000000e-11
GCST007383_20	Plasma free amino acid levels (adjusted for one other PFAA)	2.000000e-45
GCST007383_21	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-43
GCST007383_22	Plasma free amino acid levels (adjusted for one other PFAA)	2.000000e-43
GCST007383_23	Plasma free amino acid levels (adjusted for one other PFAA)	9.000000e-41
GCST007383_24	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-39
GCST007383_26	Plasma free amino acid levels (adjusted for one other PFAA)	7.000000e-19
GCST007383_62	Plasma free amino acid levels (adjusted for one other PFAA)	3.000000e-06
GCST007383_75	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-08
GCST007383_80	Plasma free amino acid levels (adjusted for one other PFAA)	5.000000e-10
GCST007383_82	Plasma free amino acid levels (adjusted for one other PFAA)	6.000000e-14
GCST007384_1	Plasma free proline levels	2.000000e-54
GCST009698_23	Metabolite levels	1.000000e-63
GCST009893_2	Serum metabolite levels	1.000000e-19
GCST012020_509	Serum metabolite levels	2.000000e-11
GCST012020_510	Serum metabolite levels	2.000000e-25
GCST012020_511	Serum metabolite levels	4.000000e-53
GCST90002398_73	Neutrophil count	2.000000e-09
GCST90002402_639	Platelet count	4.000000e-12
GCST90002407_190	White blood cell count	6.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0005134	amino acid measurement
EFO:0009765	alanine measurement
EFO:0005001	phenylalanine measurement
EFO:0009770	leucine measurement
EFO:0009769	histidine measurement
EFO:0009775	threonine measurement
EFO:0005058	tyrosine measurement
EFO:0004833	neutrophil count
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004062	DiGeorge Syndrome	C05.660.207.103.500; C14.240.400.021.500; C14.280.400.044.500; C15.604.451.249.500; C16.131.077.019.500; C16.131.240.400.021.500; C16.131.260.019.500; C16.131.482.249.500; C16.131.621.207.103.500; C16.320.180.019.500; C19.642.482.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Troglitazone	decreases activity, decreases reaction, affects abundance, increases reaction, increases activity (+4 more)	4
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	4
sodium arsenite	increases expression	2
entinostat	increases expression, affects cotreatment	2
2-chloro-5-nitrobenzanilide	decreases activity, decreases reaction, increases expression, affects binding	2
Panobinostat	affects cotreatment, increases expression	2
Cisplatin	increases expression, increases reaction, affects response to substance	2
Estradiol	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression	2
Valproic Acid	increases expression	2
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	increases expression	1
sotorasib	affects cotreatment, increases expression	1
methyleugenol	decreases expression	1
afimoxifene	decreases expression	1
bisphenol A diglycidyl ether	increases expression, decreases reaction	1
aflatoxin B2	increases methylation	1
ciglitazone	increases expression	1
benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone	decreases activity, decreases response to substance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
15-deoxyprostaglandin J2	increases expression	1
nutlin 3	increases expression, affects cotreatment	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester	affects response to substance, increases expression, decreases reaction	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases reaction, increases expression	1
trametinib	increases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, increases expression	1
Rosiglitazone	affects response to substance, decreases reaction, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7K1	MCF-7 PRODH KO	Cancer cell line	Female
CVCL_TH18	HAP1 PRODH (-) 1	Cancer cell line	Male
CVCL_XR90	HAP1 PRODH (-) 2	Cancer cell line	Male
CVCL_XR91	HAP1 PRODH (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00576407	PHASE2	COMPLETED	Thymus Transplantation in DiGeorge Syndrome #668
NCT00576836	PHASE2	COMPLETED	Thymus Transplantation Dose in DiGeorge #932
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT05149898	PHASE2	COMPLETED	Open-Label Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome (INSPIRE)
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00566488	PHASE1	COMPLETED	Parathyroid and Thymus Transplantation in DiGeorge #931
NCT00579709	PHASE1	COMPLETED	Thymus Transplantation With Immunosuppression
NCT00849888	PHASE1	TERMINATED	Serum-Free Thymus Transplantation in DiGeorge Anomaly
NCT02895906	PHASE1	COMPLETED	Safety and Efficacy Study of NFC-1 in Subjects Aged 12-17 Years With 22q11.2DS & Associated Neuropsychiatric Conditions
NCT00579527	PHASE1/PHASE2	COMPLETED	Phase I/II Thymus Transplantation With Immunosuppression #950
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00005102	Not specified	UNKNOWN	Immunologic Evaluation in Patients With DiGeorge Syndrome or Velocardiofacial Syndrome
NCT00105274	Not specified	COMPLETED	Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
NCT00278005	Not specified	TERMINATED	Infection in DiGeorge Following CHD Surgery
NCT00556530	Not specified	RECRUITING	Examining Genetic Factors That Affect the Severity of 22q11.2 Deletion Syndrome
NCT00916955	Not specified	COMPLETED	Genetic Modifiers for 22q11.2 Syndrome
NCT01220531	Not specified	COMPLETED	Thymus Transplantation Safety-Efficacy
NCT01781923	Not specified	COMPLETED	Cognitive Remediation in 22q11DS
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02460328	Not specified	COMPLETED	Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome
NCT02787486	Not specified	COMPLETED	Expanded Noninvasive Genomic Medical Assessment: The Enigma Study
NCT03284060	Not specified	TERMINATED	Social Cognition Training and Cognitive Remediation
NCT04141540	Not specified	COMPLETED	Molecular Variants Associated With Schizophrenia: Differential Analysis of Monozygotic Twins With Variable Phenotypic 22q11
NCT04373226	Not specified	TERMINATED	Arithmetic Abilities in Children With 22q11.2DS
NCT04639388	Not specified	RECRUITING	Understanding of Psychotic Disorders in Children With 22q11.2DS
NCT04639960	Not specified	TERMINATED	Neuroprotective Effects of Risperdal on Brain and Cognition in 22q11 Deletion Syndrome
NCT04647500	Not specified	COMPLETED	Effects of Methylphenidate on Brain and Cognition in 22q11 Deletion Syndrome
NCT05924347	Not specified	RECRUITING	Early Scoliotic Changes in Children at Increased Risk for Scoliosis Development
NCT07493096	Not specified	RECRUITING	Intensive Multimodal Neurorehabilitation Targeting Neuroplasticity in Pediatric Neurodevelopmental and Chromosomal Disorders