OPLAH

Summary

OPLAH (5-oxoprolinase, ATP-hydrolysing, HGNC:8149) is a protein-coding gene on chromosome 8q24.3, encoding 5-oxoprolinase (O14841). Catalyzes the cleavage of 5-oxo-L-proline to form L-glutamate coupled to the hydrolysis of ATP to ADP and inorganic phosphate.

The protein encoded by this gene acts as a homodimer, using ATP hydrolysis to catalyze the conversion of 5-oxo-L-proline to L-glutamate. Defects in this gene are a cause of 5-oxoprolinase deficiency (OPLAHD).

Source: NCBI Gene 26873 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 5-oxoprolinase deficiency (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 653 total — 20 pathogenic, 22 likely-pathogenic (top 5% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈1% of expected missense variation)
• GTEx eGene: eQTL in 12 tissues, sQTL in 5 (q < 0.05)
• Phenotypes (HPO): 26
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.16 (unconstrained)
• MANE Select transcript: NM_017570

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8149
Approved symbol	OPLAH
Name	5-oxoprolinase, ATP-hydrolysing
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	OPLA, 5-Opase
Ensembl gene	ENSG00000178814
Ensembl biotype	protein_coding
OMIM	614243
Entrez	26873

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 33 protein_coding, 9 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000618853

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 5: 2

ENST00000618853, ENST00000527993, ENST00000531027, ENST00000567871, ENST00000894953, ENST00000894954, ENST00000894955, ENST00000894956, ENST00000894957, ENST00000894958, ENST00000894959, ENST00000894960, ENST00000894961, ENST00000894962, ENST00000894963, ENST00000894964, ENST00000894965, ENST00000894966, ENST00000919620, ENST00000971668, ENST00000971669, ENST00000971670, ENST00000971671, ENST00000971672, ENST00000971673, ENST00000971674, ENST00000971675, ENST00000971676, ENST00000971677, ENST00000971678, ENST00000971679, ENST00000971680, ENST00000971681, ENST00000971682, ENST00000996961, ENST00001036813, ENST00001036815, ENST00001036817, ENST00001036819, ENST00001036821, ENST00001036822, ENST00001088111, ENST00001088112, ENST00001137316

RefSeq mRNA: 1 — MANE Select: NM_017570 NM_017570

CCDS: CCDS75802

Canonical transcript exons

ENST00000618853 — 27 exons

Exon	Start	End
ENSE00002601182	144058773	144058896
ENSE00002613541	144058496	144058691
ENSE00002616323	144058239	144058404
ENSE00003489696	144058980	144059079
ENSE00003546594	144059599	144059790
ENSE00003624579	144059862	144060085
ENSE00003714833	144052983	144053129
ENSE00003715520	144051729	144051826
ENSE00003718139	144051916	144052076
ENSE00003720937	144054812	144054913
ENSE00003721768	144055788	144055939
ENSE00003725858	144054561	144054735
ENSE00003730193	144060653	144060692
ENSE00003730662	144053209	144053393
ENSE00003731328	144052169	144052326
ENSE00003733209	144056948	144057118
ENSE00003733719	144051266	144051472
ENSE00003739282	144058010	144058148
ENSE00003740140	144057856	144057923
ENSE00003740799	144055029	144055189
ENSE00003741166	144052449	144052598
ENSE00003741275	144056147	144056259
ENSE00003742414	144057208	144057320
ENSE00003742542	144056618	144056755
ENSE00003744508	144052766	144052900
ENSE00003745488	144056385	144056523
ENSE00003748898	144057448	144057713

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 96.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.6594 / max 219.5208, expressed in 1369 samples.

Highest expression (Bgee): apex of heart, testis, atrium auricular region, lobe of liver, cardiac atrium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

OPLAH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

17 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	4.1e-16	+0.31	8:144063745:A:G
Esophagus Mucosa	eqtl	1.0e-06	-0.23	8:144060021:G:C
Muscle Skeletal	sqtl	6.5e-06	-0.45	8:144073987:A:G
Skin Sun Exposed Lower leg	eqtl	3.4e-05	+0.22	8:144125424:A:G
Colon Sigmoid	eqtl	4.5e-03	-0.48	8:143712261:G:A
Skin Not Sun Exposed Suprapubic	eqtl	5.3e-03	+0.10	8:144044402:C:T
Thyroid	sqtl	5.9e-03	-1.24	8:143120541:G:C
Breast Mammary Tissue	sqtl	7.5e-03	-1.61	8:143325505:T:C
Vagina	eqtl	9.3e-03	+0.38	8:143218467:G:T
Thyroid	eqtl	1.1e-02	+0.39	8:144949900:G:A
Minor Salivary Gland	eqtl	1.7e-02	-0.28	8:144070360:A:C
Testis	eqtl	1.8e-02	-0.24	8:144225647:G:A
Brain Nucleus accumbens basal ganglia	eqtl	2.3e-02	+0.31	8:144273390:A:G
Adrenal Gland	eqtl	2.4e-02	-0.35	8:143959591:G:A
Heart Atrial Appendage	sqtl	2.8e-02	+0.66	8:144064265:T:C
Testis	sqtl	2.9e-02	-1.55	8:145021326:T:A
Whole Blood	eqtl	3.4e-02	-0.18	8:144659757:A:G

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
95604	5.0968	1058
95605	1.6259	796
95606	0.7088	317
95609	0.1205	6
95608	0.0948	51
95610	0.0126	4

Top tissues by expression

showing 100 of 275 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	96.67	gold quality
right testis	UBERON:0004534	94.49	gold quality
left testis	UBERON:0004533	94.35	gold quality
right atrium auricular region	UBERON:0006631	93.68	gold quality
right lobe of liver	UBERON:0001114	91.53	gold quality
cardiac atrium	UBERON:0002081	91.43	gold quality
gastrocnemius	UBERON:0001388	91.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.21	gold quality
testis	UBERON:0000473	91.03	gold quality
heart left ventricle	UBERON:0002084	90.66	gold quality
cardiac ventricle	UBERON:0002082	90.06	gold quality
muscle of leg	UBERON:0001383	89.69	gold quality
body of stomach	UBERON:0001161	88.80	gold quality
transverse colon	UBERON:0001157	87.90	gold quality
mucosa of transverse colon	UBERON:0004991	87.90	gold quality
right adrenal gland cortex	UBERON:0035827	87.28	gold quality
metanephros cortex	UBERON:0010533	87.20	gold quality
heart	UBERON:0000948	86.98	gold quality
right adrenal gland	UBERON:0001233	86.66	gold quality
left adrenal gland cortex	UBERON:0035825	86.15	gold quality
left adrenal gland	UBERON:0001234	86.08	gold quality
esophagus mucosa	UBERON:0002469	85.41	gold quality
lower esophagus mucosa	UBERON:0035834	85.09	gold quality
skin of abdomen	UBERON:0001416	85.04	gold quality
adrenal cortex	UBERON:0001235	84.87	gold quality
muscle organ	UBERON:0001630	84.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.41	gold quality
minor salivary gland	UBERON:0001830	83.79	gold quality
esophagus	UBERON:0001043	83.56	gold quality
stomach	UBERON:0000945	83.24	gold quality
skin of leg	UBERON:0001511	82.76	gold quality
liver	UBERON:0002107	82.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.65	gold quality
adrenal gland	UBERON:0002369	82.63	gold quality
lower esophagus	UBERON:0013473	82.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.03	gold quality
small intestine	UBERON:0002108	81.98	gold quality
mouth mucosa	UBERON:0003729	81.82	gold quality
saliva-secreting gland	UBERON:0001044	81.47	gold quality
fundus of stomach	UBERON:0001160	81.42	gold quality
omental fat pad	UBERON:0010414	81.12	gold quality
peritoneum	UBERON:0002358	81.04	gold quality
colon	UBERON:0001155	80.98	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	80.82	gold quality
body of pancreas	UBERON:0001150	80.76	gold quality
right ovary	UBERON:0002118	80.71	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.65	gold quality
cerebellar hemisphere	UBERON:0002245	80.40	gold quality
adult mammalian kidney	UBERON:0000082	80.31	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.29	gold quality
zone of skin	UBERON:0000014	80.20	gold quality
cerebellar cortex	UBERON:0002129	80.14	gold quality
large intestine	UBERON:0000059	80.12	gold quality
intestine	UBERON:0000160	79.90	gold quality
mucosa of stomach	UBERON:0001199	79.73	gold quality
sigmoid colon	UBERON:0001159	79.27	gold quality
upper lobe of left lung	UBERON:0008952	78.95	gold quality
ectocervix	UBERON:0012249	78.95	gold quality
duodenum	UBERON:0002114	78.79	gold quality
left ovary	UBERON:0002119	78.76	gold quality
spleen	UBERON:0002106	78.67	gold quality
right lobe of thyroid gland	UBERON:0001119	78.64	gold quality
right lung	UBERON:0002167	78.32	gold quality
left uterine tube	UBERON:0001303	78.31	gold quality
spinal cord	UBERON:0002240	77.59	gold quality
cerebellum	UBERON:0002037	77.55	gold quality
tibial nerve	UBERON:0001323	77.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	77.10	gold quality
adipose tissue	UBERON:0001013	77.04	gold quality
left lobe of thyroid gland	UBERON:0001120	77.04	gold quality
upper lobe of lung	UBERON:0008948	76.82	gold quality
vagina	UBERON:0000996	76.62	gold quality
stromal cell of endometrium	CL:0002255	76.53	gold quality
cortex of kidney	UBERON:0001225	76.10	gold quality
connective tissue	UBERON:0002384	75.88	gold quality
ventricular zone	UBERON:0003053	75.73	gold quality
right frontal lobe	UBERON:0002810	75.61	gold quality
amygdala	UBERON:0001876	75.54	gold quality
anatomical system	UBERON:0000467	75.00	gold quality
thyroid gland	UBERON:0002046	74.97	gold quality
multicellular organism	UBERON:0000468	74.88	gold quality
material anatomical entity	UBERON:0000465	74.85	gold quality
heart right ventricle	UBERON:0002080	74.74	gold quality
endocervix	UBERON:0000458	74.49	gold quality
skeletal muscle tissue	UBERON:0001134	74.17	gold quality
prostate gland	UBERON:0002367	74.12	gold quality
caudate nucleus	UBERON:0001873	73.87	gold quality
blood	UBERON:0000178	73.83	gold quality
monocyte	CL:0000576	73.65	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	73.64	gold quality
putamen	UBERON:0001874	73.60	gold quality
mononuclear cell	CL:0000842	73.43	gold quality
body of uterus	UBERON:0009853	73.26	gold quality
leukocyte	CL:0000738	73.12	gold quality
gall bladder	UBERON:0002110	72.99	gold quality
kidney	UBERON:0002113	72.94	gold quality
ovary	UBERON:0000992	72.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.47	gold quality
granulocyte	CL:0000094	72.46	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.10

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Skeletal muscle	tissue	31.1
Testis	tissue	28.7
Choroid plexus	tissue	19.4
Frontal cortex	tissue	15.2
Caudate putamen	tissue	14.9
Heart muscle	tissue	14.5
Tongue	tissue	14.4
Duodenum	tissue	13.0
Locus coeruleus	tissue	13.0
Hippocampus	tissue	12.7
Salivary gland	tissue	10.1
Liver	tissue	9.3
Vagina	tissue	8.7
Nucleus accumbens	tissue	8.7
Small intestine	tissue	8.3
Stomach 1	tissue	8.2
Thalamus	tissue	7.6
Superior colliculi	tissue	7.5
Pons	tissue	6.9
Postcentral gyrus	tissue	6.8
Adipose tissue	tissue	6.6
Pancreas	tissue	6.5
Parathyroid gland	tissue	6.3
Midbrain	tissue	6.3
Skin 1	tissue	6.1
Cerebellum	tissue	5.7
Kidney	tissue	5.6
Seminal vesicle	tissue	5.4
Colon	tissue	5.3
Substantia nigra	tissue	5.3
Medulla oblongata	tissue	5.2
Adrenal gland	tissue	4.8
Basal ganglia	tissue	4.7
Cerebral cortex	tissue	4.6
Somatosensory cortex	tissue	4.6
Hypothalamus	tissue	4.5
Periaqueductal gray	tissue	4.5
Motor cortex	tissue	4.4
Spinal cord	tissue	4.4
Putamen	tissue	4.3
Esophagus	tissue	4.0
Ventral forebrain	tissue	4.0
Retrosplenial cortex	tissue	4.0
Prefrontal cortex	tissue	3.9
Occipital cortex	tissue	3.9
Septum	tissue	3.8
Hippocampal formation	tissue	3.7
Retrosplenial and cingulate cortex	tissue	3.7
Entorhinal cortex	tissue	3.6
Insular cortex	tissue	3.6
Prostate	tissue	3.5
Temporal cortex	tissue	3.3
Amygdala	tissue	3.1
Spleen	tissue	3.1
Pituitary gland	tissue	3.0
Olfactory bulb	tissue	2.8
Bone marrow	tissue	2.5
Gallbladder	tissue	2.3
Rectum	tissue	2.0
Corpus callosum	tissue	1.9

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Principal sensory trigeminal nucleus (34.3), Nucleus raphe magnus (33.4), Nuclei of the trapezoid body (30.8), Ventral periolivary nuclei (28.9), Pontine nuclei (27.3).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 1.05e-35, LOEUF 1.16, missense Z -1.87 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000618853 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈1% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
8:144,051,329–144,059,035	1726 / 1642.1	1.05	no
8:144,059,036–144,059,611	8 / 23.9	0.34	yes (p 1.2e-03)
8:144,059,612–144,060,032	168 / 170.6	0.98	no

Literature-anchored findings (GeneRIF, showing 3)

• the cause of cellular ATP depletion in nephrotic cystinosis may be the futile cycle, formed between two ATP-dependant gamma-glutamyl cycle enzymes, gamma-glutamyl cysteine synthetase and 5-oxoprolinase (PMID:20413906)
• In this study, clinical, biochemical, and genetic aspects of five Chinese 5-oxoprolinuria patients with OPLAH or GSS gene mutations were investigated. (PMID:25851806)
• An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes (PMID:27477828)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	oplah	ENSDARG00000045123
mus_musculus	Oplah	ENSMUSG00000022562
rattus_norvegicus	Oplah	ENSRNOG00000011781
drosophila_melanogaster	CG4752	FBGN0034733
caenorhabditis_elegans		WBGENE00021430

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1922725) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal lens morphology	1
cataract	1
increased startle reflex	1
decreased heart rate	1
decreased red blood cell distribution width	1
decreased circulating unsaturated transferrin level	1
decreased total retina thickness	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q75WB5	94.4%	Diamond
Arabidopsis thaliana	Q9FIZ7	57.8%	Diamond
Saccharomyces cerevisiae S288C	P28273	56.4%	Diamond
Schizosaccharomyces pombe 972h-	Q10094	56.4%	Diamond
Dictyostelium discoideum	Q54NW6	55.0%	Diamond
Pestalotiopsis fici W106-1	W3X7R6	48.5%	Diamond
Pseudomonas sp. NS671	Q01262	35.6%	Diamond
Methanocaldococcus jannaschii DSM 2661	Q58373	34.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR6847	ncRNA	102465510
EXOSC4	protein-coding	54512
GPAA1	protein-coding	8733
MIR6846	ncRNA	102465509
CYC1	protein-coding	1537
SPATC1	protein-coding	375686
PARP10	protein-coding	84875
GRINA	protein-coding	2907
PLEC	protein-coding	5339
MIR661	ncRNA	724031
SHARPIN	protein-coding	81858
EPPK1	protein-coding	83481

Protein

Protein identifiers

5-oxoprolinase — O14841 (reviewed: O14841)

Alternative names: 5-oxo-L-prolinase, Pyroglutamase

All UniProt accessions (2): A0A087WY99, O14841

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the cleavage of 5-oxo-L-proline to form L-glutamate coupled to the hydrolysis of ATP to ADP and inorganic phosphate.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. 5-oxoprolinase deficiency (OPLAHD) [MIM:260005] A disorder characterized by calcium oxalate/carbonate urolithiasis, and excessive urinary 5-oxo-L-proline. Affected individuals have recurrent episodes of vomiting, diarrhea, and abdominal pain. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the oxoprolinase family.

RefSeq proteins (1): NP_060040* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002821	Hydantoinase_A	Domain
IPR003692	Hydantoinase_B	Domain
IPR008040	Hydant_A_N	Domain
IPR045079	Oxoprolinase-like	Family
IPR049517	ACX-like_C	Domain

Pfam: PF01968, PF02538, PF05378, PF19278

Enzyme classification (BRENDA)

• EC 3.5.2.9 — 5-oxoprolinase (ATP-hydrolysing) (BRENDA: 29 organisms, 51 substrates, 21 inhibitors, 39 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
5-OXOPROLINE	0.0316–0.58	12
ATP	0.03–1	8
5-OXO-L-PROLINE	0.005–0.0511	6
ITP	0.13–0.41	4
MGATP2-	0.1–4.2	4
UTP	0.17–1.11	2
L-2-OXOTHIAZOLIDINE-4-CARBOXYLATE	0.17	1
L-2-OXOTHIAZOLIDINE-4-CARBOXYLIC ACID	0.002	1
MNATP2-	0.5	1

Catalyzed reactions (Rhea)

• 5-oxo-L-proline + ATP + 2 H2O = L-glutamate + ADP + phosphate + H(+) (RHEA:10348)

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

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14841-F1	88.08	0.58

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of amino acid metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoli fibrillar center

Antibody reliability (HPA): IH uncertain · IF approved

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)

Type	Positions
Phosphothreonine	151
Phosphoserine	1265

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 9; 4 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-5578998	Defective OPLAH causes OPLAHD ⚕	curated
R-HSA-174403	Glutathione synthesis and recycling	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5668914	Diseases of metabolism ⚕	—
R-HSA-5579029	Metabolic disorders of biological oxidation enzymes ⚕	—
R-HSA-211859	Biological oxidations	—
R-HSA-156590	Glutathione conjugation	—
R-HSA-1430728	Metabolism	—
R-HSA-156580	Phase II - Conjugation of compounds	—

MSigDB gene sets: 184 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, MORF_MSH3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, KANG_FLUOROURACIL_RESISTANCE_DN, GOBP_AMIDE_METABOLIC_PROCESS, REACTOME_GLUTATHIONE_CONJUGATION, GOBP_GLUTATHIONE_METABOLIC_PROCESS, GOBP_MODIFIED_AMINO_ACID_METABOLIC_PROCESS, MORF_PRKACA, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, SANSOM_APC_MYC_TARGETS, MORF_KDR, NIKOLSKY_BREAST_CANCER_8Q23_Q24_AMPLICON, KEGG_GLUTATHIONE_METABOLISM

GO Biological Process (2): glutathione metabolic process (GO:0006749), glutathione catabolic process (GO:0006751)

GO Molecular Function (7): ATP binding (GO:0005524), 5-oxoprolinase (ATP-hydrolyzing) activity (GO:0017168), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Glutathione conjugation	1
Metabolic disorders of biological oxidation enzymes	1
Biological oxidations	1
Phase II - Conjugation of compounds	1
Metabolism	1
Diseases of metabolism	1
Disease	1

GO top-level categories

17 GO namespaces:

Category	Terms
modified amino acid metabolic process	1
sulfur compound metabolic process	1
glutathione metabolic process	1
modified amino acid catabolic process	1
sulfur compound catabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 10 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 19 of 940 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OPLAH	GGCT	O75223	717
OPLAH	GRINA	Q7Z429	530
OPLAH	GSS	P48637	519
OPLAH	CNDP2	Q96KP4	455
OPLAH	CHAC2	Q8WUX2	435
OPLAH	GPAA1	O43292	435
OPLAH	GGT5	P36269	434
OPLAH	TMEM276	P0DTL5	415
OPLAH	SPATC1	Q76KD6	401
OPLAH	PDK4	Q16654	390
OPLAH	CHAC1	Q9BUX1	373
OPLAH	SFRP2	Q96HF1	370
OPLAH	TFE3	P19532	370
OPLAH	QPCT	Q16769	370
OPLAH	TPBG	Q13641	370
OPLAH	PPP2R2C	Q9Y2T4	370
OPLAH	CELF4	Q9BZC1	370
OPLAH	ZFP90	Q8TF47	370
OPLAH	TPBGL	P0DKB5	370

IntAct

Human interaction partners of OPLAH in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
POU6F2	physical association	0.560	3
TPK1	physical association	0.560	3
GK	physical association	0.370	1
HOXA1	physical association	0.370	1

BioGRID (14 interactions; top human partners by supporting records): GK (Two-hybrid), HOXA1 (Two-hybrid), MAPT (Affinity Capture-MS), POU6F2 (Two-hybrid), PTGES2 (Affinity Capture-MS), RECQL4 (Affinity Capture-MS), TPK1 (Two-hybrid), TRIM67 (Affinity Capture-MS), UBC (Reconstituted Complex), ZNF451 (Two-hybrid), ZRANB1 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for OPLAH: 653 ClinVar records (42 pathogenic / likely pathogenic); 8 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	22
Uncertain significance	325
Likely benign	195
Benign	40

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 42 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
31133	NM_017570.5(OPLAH):c.2608dup (p.His870fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
3595434	NM_017570.5(OPLAH):c.744C>A (p.Tyr248Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
504164	NM_017570.5(OPLAH):c.587+1G>C	Pathogenic	criteria provided, single submitter	1
572337	NM_017570.5(OPLAH):c.2557C>T (p.Arg853Ter)	Pathogenic	criteria provided, single submitter	1
856398	NM_017570.5(OPLAH):c.493C>T (p.Gln165Ter)	Pathogenic	criteria provided, single submitter	1
955289	NM_017570.5(OPLAH):c.2987dup (p.Arg997fs)	Pathogenic	criteria provided, single submitter	1
1179092	NM_017570.5(OPLAH):c.2076C>A (p.Cys692Ter)	Pathogenic	criteria provided, single submitter	1
2037024	NM_017570.5(OPLAH):c.206_251dup (p.Thr85fs)	Pathogenic	criteria provided, single submitter	1
2194554	NM_017570.5(OPLAH):c.3612C>G (p.Tyr1204Ter)	Pathogenic	criteria provided, single submitter	1
2770865	NM_017570.5(OPLAH):c.2677C>T (p.Gln893Ter)	Pathogenic	criteria provided, single submitter	1
2776954	NM_017570.5(OPLAH):c.2362dup (p.His788fs)	Pathogenic	criteria provided, single submitter	1
2835035	NM_017570.5(OPLAH):c.1652del (p.Leu551fs)	Pathogenic	criteria provided, single submitter	1
2870863	NM_017570.5(OPLAH):c.2669del (p.Gly890fs)	Pathogenic	criteria provided, single submitter	1
3017064	NM_017570.5(OPLAH):c.3249_3250delinsTT (p.Gln1084Ter)	Pathogenic	criteria provided, single submitter	1
3600351	NM_017570.5(OPLAH):c.3081dup (p.Arg1028fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore OPLAH’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 20 predictions of 1,965):

Position(s)	Effect	Δscore	Sites
8:144051727	donor_loss	1.0000	2
8:144052077	acceptor_loss	1.0000
8:144052087	acceptor_gain	1.0000
8:144052167–144052168	donor_loss	1.0000	2
8:144052764–144052765	donor_loss	1.0000	5
8:144052912	acceptor_gain	1.0000
8:144052982	donor_loss	1.0000	2
8:144052997	donor_gain	1.0000
8:144053130–144053131	acceptor_loss	1.0000	4
8:144054617	donor_gain	1.0000

AlphaMissense

3,362 missense substitutions predicted likely pathogenic (of 8,282 scored), across 838 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M752	9	0.963	0.996
M315	9	0.910	0.984
M465	9	0.906	0.995
M1140	9	0.866	0.986
M268	9	0.860	0.978
D770	8	0.997	0.999
D831	8	0.994	0.997
H855	8	0.993	0.999
D922	8	0.991	0.996
D314	8	0.990	0.996
D20	8	0.989	0.995
D393	8	0.988	0.997
H828	8	0.988	0.998
D321	8	0.986	0.992
F18	8	0.983	0.998
H792	8	0.983	0.998
D13	8	0.982	0.991
D1147	8	0.981	0.991
F776	8	0.975	0.996
F410	8	0.970	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	4.21e-05
Glioblastoma Multiforme (validation)	unfavorable	0.000215
Ovary Serous Cystadenocarcinoma (validation)	favorable	0.000325
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000934

Disease associations

OMIM: gene MIM:614243 | disease phenotypes: MIM:260005

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
5-oxoprolinase deficiency	Strong	Autosomal recessive	3

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Hypotonic infant	amber
Leukodystrophy, childhood onset	amber
Likely inborn error of metabolism	amber
Paediatric disorders	amber
Undiagnosed metabolic disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (1): 5-oxoprolinase deficiency (MONDO:0009825)

Orphanet (1): 5-oxoprolinase deficiency (Orphanet:33572)

HPO phenotypes

26 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000750	Delayed speech and language development
HP:0000787	Kidney stone
HP:0000952	Jaundice
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0002059	Cerebral atrophy
HP:0003137	Prolinuria
HP:0004387	Enterocolitis
HP:0005490	Postnatal macrocephaly
HP:0008672	Calcium oxalate nephrolithiasis
HP:0008872	Feeding difficulties in infancy
HP:0008947	Floppy infant
HP:0040142	Reduced circulating 5-oxoprolinase activity
HP:0410132	Increased level of L-pyroglutamic acid in urine

GWAS associations

8 associations:

Study	Trait	p-value
GCST012020_225	Serum metabolite levels	4e-100
GCST001217_16	Metabolic traits	2e-59
GCST012020_425	Serum metabolite levels	6e-58
GCST006249_7	Serum metabolite levels	8e-51
GCST90002397_305	Mean spheric corpuscular volume	1e-31
GCST012353_30	Serum metabolite concentrations in chronic kidney disease	2e-22
GCST008115_38	Bipolar I disorder	2e-8
GCST008103_69	Bipolar disorder	1e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0009963	bipolar I disorder

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C535322	5-oxoprolinase deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
bisphenol A	affects expression, affects cotreatment, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
Aflatoxin B1	affects expression, decreases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
bismuth tripotassium dicitrate	decreases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
mercuric bromide	affects cotreatment, decreases 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
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
belinostat	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.