POR

Summary

POR (cytochrome p450 oxidoreductase, HGNC:9208) is a protein-coding gene on chromosome 7q11.23, encoding NADPH–cytochrome P450 reductase (P16435). This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes.

This gene encodes an endoplasmic reticulum membrane oxidoreductase that is essential for multiple metabolic processes, including reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. The encoded protein has a flavin adenine dinucleotide (FAD)-binding domain and a flavodoxin-like domain which bind two cofactors, FAD and FMN, that allow it to donate electrons directly from NADPH to all microsomal P450 enzymes. Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase, 21-hydroxylase, and 17 alpha-hydroxylase.

Source: NCBI Gene 5447 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 905 total — 59 pathogenic, 34 likely-pathogenic (top 3% of genes corpus-wide)
• GTEx eGene: eQTL in 38 tissues, sQTL in 14 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.89 (unconstrained)
• MANE Select transcript: NM_001395413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9208
Approved symbol	POR
Name	cytochrome p450 oxidoreductase
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	CYPOR, FLJ26468
Ensembl gene	ENSG00000127948
Ensembl biotype	protein_coding
OMIM	124015
Entrez	5447

Gene structure

Transcript identifiers

Ensembl transcripts: 75 — 50 protein_coding, 19 nonsense_mediated_decay, 6 retained_intron

MANE Select: ENST00000461988

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 6, TSL 3: 3, TSL 4: 9, TSL 5: 5

ENST00000461988, ENST00000394893, ENST00000412064, ENST00000412521, ENST00000414186, ENST00000418341, ENST00000421059, ENST00000426184, ENST00000432753, ENST00000439269, ENST00000439297, ENST00000439963, ENST00000447222, ENST00000448410, ENST00000449920, ENST00000453773, ENST00000454934, ENST00000460892, ENST00000471238, ENST00000475509, ENST00000487247, ENST00000493973, ENST00000495770, ENST00000496888, ENST00000706544, ENST00000706545, ENST00000706546, ENST00000706547, ENST00000910546, ENST00000910547, ENST00000910548, ENST00000910549, ENST00000910550, ENST00000910551, ENST00000910552, ENST00000910553, ENST00000910554, ENST00000910555, ENST00000910556, ENST00000910557, ENST00000910558, ENST00000910559, ENST00000910560, ENST00000910561, ENST00000910562, ENST00000910563, ENST00000910564, ENST00000933049, ENST00000933050, ENST00000944612, ENST00000944613, ENST00000944614, ENST00000944615, ENST00000944616, ENST00000997439, ENST00000997440, ENST00000997441, ENST00000997442, ENST00000997443, ENST00000997445, ENST00000997446, ENST00000997448, ENST00000997450, ENST00000997453, ENST00001027547, ENST00001027549, ENST00001076919, ENST00001076920, ENST00001076921, ENST00001076922, ENST00001076923, ENST00001076924, ENST00001076925, ENST00001116913, ENST00001116914

RefSeq mRNA: 7 — MANE Select: NM_001395413 NM_001367562, NM_001382655, NM_001382657, NM_001382658, NM_001382659, NM_001382662, NM_001395413

CCDS: CCDS5579

Canonical transcript exons

ENST00000461988 — 16 exons

Exon	Start	End
ENSE00003490746	75984777	75984958
ENSE00003520396	75953989	75954180
ENSE00003526398	75972413	75972461
ENSE00003543851	75979451	75979579
ENSE00003549389	75982224	75982322
ENSE00003572657	75981048	75981172
ENSE00003585469	75983520	75983636
ENSE00003588129	75986159	75986241
ENSE00003608871	75985058	75985207
ENSE00003633024	75985923	75986068
ENSE00003653277	75981517	75981606
ENSE00003653353	75985579	75985849
ENSE00003669121	75983738	75983856
ENSE00003786242	75980339	75980488
ENSE00003996125	75915155	75915179
ENSE00003996127	75986337	75986855

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.2134 / max 827.9743, expressed in 1807 samples.

Highest expression (Bgee): adrenal tissue, lobe of liver, adrenal gland, adrenal gland cortex, adrenal cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POR is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 14 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 52 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	sqtl	8.4e-57	-0.91	7:75982438:C:T
Esophagus Gastroesophageal Junction	eqtl	8.6e-22	+0.42	7:75985459:G:A
Artery Aorta	eqtl	1.5e-21	+0.43	7:75985459:G:A
Esophagus Muscularis	eqtl	3.7e-20	+0.38	7:75985459:G:A
Testis	eqtl	1.0e-18	+0.31	7:75917574:G:A
Brain Cerebellar Hemisphere	eqtl	1.3e-16	-0.87	7:75914929:C:A
Colon Sigmoid	eqtl	3.4e-16	+0.39	7:75985459:G:A
Cells Cultured fibroblasts	eqtl	1.0e-15	+0.26	7:75957679:T:A
Cells EBV-transformed lymphocytes	eqtl	1.6e-14	+0.42	7:75917574:G:A
Nerve Tibial	eqtl	1.2e-13	+0.24	7:75985459:G:A
Whole Blood	eqtl	4.9e-13	+0.11	7:75985459:G:A
Lung	eqtl	3.4e-12	+0.25	7:76214206:T:C
Spleen	eqtl	2.7e-11	+0.31	7:75985459:G:A
Thyroid	eqtl	3.6e-11	+0.18	7:75985459:G:A
Muscle Skeletal	eqtl	8.8e-11	+0.15	7:75915137:A:C
Brain Cerebellum	eqtl	1.7e-10	-0.82	7:75905645:A:G
Artery Tibial	eqtl	3.2e-10	-0.36	7:75905645:A:G
Lung	sqtl	9.3e-09	+0.37	7:75984680:C:T
Skin Sun Exposed Lower leg	eqtl	2.2e-08	+0.12	7:76079624:C:T
Heart Atrial Appendage	eqtl	2.9e-07	+0.24	7:75985459:G:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
79133	13.9409	1759
79132	6.2552	1742
79137	0.0173	4

Top tissues by expression

showing 100 of 289 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	99.30	gold quality
right lobe of liver	UBERON:0001114	99.27	gold quality
right adrenal gland	UBERON:0001233	99.16	gold quality
right adrenal gland cortex	UBERON:0035827	99.13	gold quality
left adrenal gland	UBERON:0001234	99.08	gold quality
left adrenal gland cortex	UBERON:0035825	99.08	gold quality
adrenal cortex	UBERON:0001235	98.92	gold quality
adrenal gland	UBERON:0002369	98.87	gold quality
right lobe of thyroid gland	UBERON:0001119	98.67	gold quality
left lobe of thyroid gland	UBERON:0001120	98.47	gold quality
adenohypophysis	UBERON:0002196	98.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.94	gold quality
thyroid gland	UBERON:0002046	97.92	gold quality
metanephros cortex	UBERON:0010533	97.75	gold quality
pituitary gland	UBERON:0000007	97.62	gold quality
lower esophagus mucosa	UBERON:0035834	97.58	gold quality
right uterine tube	UBERON:0001302	97.53	gold quality
liver	UBERON:0002107	97.50	gold quality
mucosa of transverse colon	UBERON:0004991	97.28	gold quality
right ovary	UBERON:0002118	97.22	gold quality
upper lobe of left lung	UBERON:0008952	97.07	gold quality
left ovary	UBERON:0002119	96.72	gold quality
right lung	UBERON:0002167	96.61	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.56	gold quality
upper lobe of lung	UBERON:0008948	96.44	gold quality
left uterine tube	UBERON:0001303	96.11	gold quality
ectocervix	UBERON:0012249	96.02	gold quality
islet of Langerhans	UBERON:0000006	95.90	gold quality
endocervix	UBERON:0000458	95.85	gold quality
omental fat pad	UBERON:0010414	95.85	gold quality
small intestine	UBERON:0002108	95.83	gold quality
peritoneum	UBERON:0002358	95.77	gold quality
apex of heart	UBERON:0002098	95.70	gold quality
duodenum	UBERON:0002114	95.53	gold quality
skin of abdomen	UBERON:0001416	95.45	gold quality
esophagus mucosa	UBERON:0002469	95.38	gold quality
gall bladder	UBERON:0002110	95.29	gold quality
spleen	UBERON:0002106	95.28	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.28	gold quality
nasal cavity epithelium	UBERON:0005384	95.21	gold quality
skin of leg	UBERON:0001511	94.97	gold quality
transverse colon	UBERON:0001157	94.80	gold quality
body of stomach	UBERON:0001161	94.63	gold quality
right testis	UBERON:0004534	94.51	gold quality
left testis	UBERON:0004533	94.48	gold quality
right atrium auricular region	UBERON:0006631	94.33	gold quality
tibial nerve	UBERON:0001323	94.30	gold quality
monocyte	CL:0000576	94.20	gold quality
ascending aorta	UBERON:0001496	94.08	gold quality
esophagus	UBERON:0001043	94.06	gold quality
jejunal mucosa	UBERON:0000399	93.99	gold quality
thoracic aorta	UBERON:0001515	93.97	gold quality
left coronary artery	UBERON:0001626	93.96	gold quality
body of uterus	UBERON:0009853	93.96	gold quality
granulocyte	CL:0000094	93.87	gold quality
mononuclear cell	CL:0000842	93.80	gold quality
aorta	UBERON:0000947	93.74	gold quality
tibial artery	UBERON:0007610	93.70	gold quality
popliteal artery	UBERON:0002250	93.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.69	gold quality
leukocyte	CL:0000738	93.60	gold quality
gastrocnemius	UBERON:0001388	93.51	gold quality
heart left ventricle	UBERON:0002084	93.45	gold quality
minor salivary gland	UBERON:0001830	93.44	gold quality
descending thoracic aorta	UBERON:0002345	93.44	gold quality
right coronary artery	UBERON:0001625	93.42	gold quality
coronary artery	UBERON:0001621	93.19	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.16	gold quality
cortical plate	UBERON:0005343	93.10	gold quality
stromal cell of endometrium	CL:0002255	92.93	gold quality
cardiac ventricle	UBERON:0002082	92.89	gold quality
stomach	UBERON:0000945	92.83	gold quality
adult mammalian kidney	UBERON:0000082	92.75	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.73	gold quality
lower esophagus	UBERON:0013473	92.65	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.64	gold quality
body of pancreas	UBERON:0001150	92.61	gold quality
mucosa of stomach	UBERON:0001199	92.60	gold quality
zone of skin	UBERON:0000014	92.59	gold quality
nucleus accumbens	UBERON:0001882	92.54	gold quality
pancreas	UBERON:0001264	92.33	gold quality
testis	UBERON:0000473	92.28	gold quality
cardiac atrium	UBERON:0002081	92.22	gold quality
right frontal lobe	UBERON:0002810	92.21	gold quality
seminal vesicle	UBERON:0000998	92.20	gold quality
mouth mucosa	UBERON:0003729	92.08	gold quality
adipose tissue	UBERON:0001013	92.03	gold quality
muscle of leg	UBERON:0001383	92.02	gold quality
intestine	UBERON:0000160	91.99	gold quality
heart	UBERON:0000948	91.94	gold quality
ovary	UBERON:0000992	91.68	gold quality
amygdala	UBERON:0001876	91.66	gold quality
caudate nucleus	UBERON:0001873	91.49	gold quality
vagina	UBERON:0000996	91.42	gold quality
colon	UBERON:0001155	91.38	gold quality
cingulate cortex	UBERON:0003027	91.26	gold quality
ganglionic eminence	UBERON:0004023	91.18	gold quality
connective tissue	UBERON:0002384	91.15	gold quality
anterior cingulate cortex	UBERON:0009835	91.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 157 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	292.8	high
Adrenal gland	tissue	130.5	high
Thyroid gland	tissue	123.0	high
Seminal vesicle	tissue	106.6	high
Duodenum	tissue	99.9	high
Small intestine	tissue	87.0	high
Parathyroid gland	tissue	72.7	high
Pituitary gland	tissue	67.0
Tongue	tissue	64.8
Caudate putamen	tissue	56.3
Locus coeruleus	tissue	54.4
Frontal cortex	tissue	52.3
Esophagus	tissue	50.4	medium
Adipose tissue	tissue	50.3	medium
Nucleus accumbens	tissue	50.2
Lung	tissue	48.7	high
Hippocampus	tissue	48.1	medium
Fallopian tube	tissue	46.9	high
Placenta	tissue	43.9	high
Choroid plexus	tissue	43.3
Pancreas	tissue	42.2	medium
Frontal cortex	tissue	41.2
Postcentral gyrus	tissue	40.7
Stomach 1	tissue	39.4	high
Cervix	tissue	39.1	high
Vagina	tissue	39.0	medium
Ovary	tissue	38.4	high
Caudate putamen	tissue	37.8
Thymus	tissue	35.3
Gallbladder	tissue	34.7	high
Urinary bladder	tissue	34.5	high
Colon	tissue	33.8	high
Skin 1	tissue	33.6	high
Kidney	tissue	32.6	high
Hypothalamus	tissue	30.8
Appendix	tissue	30.5	high
Spleen	tissue	30.1	medium
Cerebellum	tissue	28.4	low
Epididymis	tissue	28.0	high
Thalamus	tissue	27.3
Superior colliculi	tissue	27.0
Spinal cord	tissue	26.7
Smooth muscle	tissue	26.6	not detected
Medulla oblongata	tissue	26.5
Pons	tissue	26.3
Midbrain	tissue	26.1
Hippocampal formation	tissue	25.8
Prostate	tissue	25.4	medium
Substantia nigra	tissue	25.1
Periaqueductal gray	tissue	24.8
Septum	tissue	24.0
Cerebral cortex	tissue	23.9	low
Somatosensory cortex	tissue	23.9
Occipital cortex	tissue	22.8
Heart muscle	tissue	22.4	not detected
Salivary gland	tissue	22.4	medium
Adrenal gland	tissue	22.3	medium
Testis	tissue	22.0	high
Tonsil	tissue	21.9	high
Corpus callosum	tissue	21.6

Brain sub-regions (HPA Brain Atlas): detected in 382; highest nTPM — Ventromedial nucleus (80.9), Arcuate nucleus (72.6), Anterior thalamic nucleus, ventral (62.5), Median raphe nucleus (61.5), Dorsomedial nucleus (59.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting POR by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

15 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-12127	97.93	66.67	793
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-6895-5P	97.05	64.96	522
HSA-MIR-134-3P	96.83	66.22	1001

Functional genomics

gnomAD constraint: pLI 8.98e-14, LOEUF 0.887, missense Z -0.355 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000461988 — one region, missense o/e 0.99.

Literature-anchored findings (GeneRIF, showing 40)

• activation of HIF-1 is modulated by cytochrome P-450 reductase in cell membrane (PMID:11971899)
• role of coenzyme binding in regulating interflavin electron transfer in human cytochrome P450 reductase (PMID:12787027)
• Molecular pathogenesis of this form of congenital adrenal hyperplasia is caused by mutations in the gene encoding P450 oxidoreductase (PMID:15220035)
• POR deficiency is a new disorder of adrenal and gonadal steroidogenesis that affects all microsomal cytochrome P450 enzymes, hence may have important implications for genetic differences in drug metabolism. (PMID:15666840)
• POR deficiency is a new disease, distinct from the craniosynostosis syndromes caused by FGFR mutations. (PMID:16467261)
• analysis of FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase (PMID:16998238)
• Antticancer activity of motexafin gadolinium may involve inhibition of this enzyme. (PMID:17018578)
• data suggest that African Americans harbor an allele at the POR locus that may increase breast cancer risk (PMID:17440066)
• A287P homozygous patients had preferential inhibition of CYP17A1, whereas Steroid 21-Hydroxylase retained near normal activity. (PMID:17505056)
• The energetics of 2’,5’-ADP binding to the FAD-binding domain of cytochrome P450 reductase were characterized. (PMID:17580970)
• Mutations R457H and V492E located in the FAD domain of NADPH P450 oxidoreductase (POR) that disrupt electron transfer caused a complete loss of CYP19A1 activity. (PMID:17595315)
• clinical, structural and functional implications of mutations and polymorphisms in POR (PMID:17635179)
• TG100435 and TG100855 were interconverted metabolically. FMO3 seem to be the major N-oxidizing enzyme, whereas cytochrome P450 reductase seems to be responsible for the retroreduction reaction. (PMID:17881660)
• The POR gene in a representative population of 842 healthy unrelated individuals in four ethnic groups was sequenced and compared. (PMID:18230729)
• The prognosis for patients with POR deficiency appears to depend on the severity of the bony malformations and their timely treatment. (PMID:18259105)
• The common P450 oxidoreductase variant A503V is not a modifier gene for 21-hydroxylase deficiency. (PMID:18397975)
• POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency. (PMID:18559916)
• patients with Antley-Bixler-like skeletal anomalies, but with mutations in the POR gene and disordered steroidogenesis, represent a new disorder called POR deficiency. (PMID:18630181)
• Experiments using excess NADPH over cytochrome P450 reductase provide evidence that both pH and solvent significantly influence the kinetic exposure of the blue di-semiquinone intermediate, yet the observed rate constants are essentially pH independent. (PMID:18681889)
• CPR’s putative membrane topology indicates that the Q153R and R316W missense mutations found in patients with disordered steroidogenesis are located within the membrane-associated regions. (PMID:19161969)
• Results describe a model of the structure of human P450 oxidoreductase created by in silico amino acid replacements in the rat POR crystal structure. (PMID:19744540)
• Data support the formation of P450c17, P450arom, and CPR homodimers and oligomers in lipid bilayers. (PMID:19805543)
• study describes 4 patients with POR deficiency & characterizes activities of their mutations; all were compound heterozygotes for POR mutations, including 5 novel mutations: L577R, N185K, delE217, and frameshift mutations 1363delC 7 697-698insGAAC (PMID:19837910)
• Domain motion in cytochrome P450 reductase: conformational equilibria revealed by NMR and small-angle x-ray scattering. (PMID:19858215)
• study concludes that compromised FMN binding is the specific molecular defect causing POR deficiency in patients with Y181D mutation and that this defect, in large part, can be overcome in vitro by FMN addition (PMID:19884324)
• Results indicate that residues in the C-helix of cytochrome P450 2B6 play a major role in the interaction with NADPH-cytochrome P450 reductase. (PMID:20096935)
• POR variants affect CYP3A4 activities. (PMID:20697309)
• Report co-expression of recombinant human CYP2C9 with human cytochrome P450 reductase in protease deficient S. cerevisiae strain at a higher scale yields an enzyme of higher specific activity. (PMID:20722625)
• mutations in POR found in patients with congenital adrenal hyperplasia may reduce HO-1 activity, potentially influencing heme catabolism in individuals carrying mutant POR alleles. (PMID:20732302)
• Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. (PMID:20844025)
• report mutations in POR in patients with disordered steroidogenesis/Antley-Bixler syndrome may reduce CYP3A4 activity; POR mutants Y181D, A457H, Y459H, V492E, R616X had over 99% loss of CYP3A4 activity; mutations A287P, C569Y, V608F lost 60-85% activity (PMID:20849814)
• kinetic studies of catalytic interaction with CYP3A4 in liposomes; data support model in which 1st electron transfer takes place within relatively stable CPR-CYP3A4 complex then complex dissociates/reforms between 1st & 2nd electron transfers (PMID:20879989)
• Cytochrome P450 oxidoreductase genetic variants have different effects on catalysis by CYP2D6 that depend on the substrate being metabolized. (PMID:20940534)
• POR is probably an important contributor to genetic variation in both steroidogenesis and drug metabolism (PMID:21070833)
• we identified 75 genetic variations in the POR gene including 26 novel ones from 235 Japanese subjects. Four novel variations resulted in amino acid substitutions. (PMID:21084761)
• POR variants may also affect skeletal development and drug metabolism. (PMID:21164260)
• investigation of influence of domain interfaces on various internal and external electron transfer rates, redox potentials of cofactors (FMN/FAD), and global geometry of the enzyme (PMID:21265736)
• the human P450 (cytochrome) oxidoreductase gene transcription is regulated by thyroid hormone receptor beta and Smad3/4 (PMID:21393444)
• Results reveal unusual biochemical differences between mosquito CPR and the human form in the binding of small molecules that may aid the development of ‘smart’ insecticides and synergists that selectively target mosquito CPR. (PMID:21655236)
• this study provides novel insights into the regulation of gap junction function by CYPOR and suggests that Cx43 may play an important role(s) in CYPOR-mediated bone defects seen in patients. (PMID:21726529)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pora	ENSDARG00000055092
danio_rerio	porb	ENSDARG00000059035
mus_musculus	Por	ENSMUSG00000005514
rattus_norvegicus	Por	ENSRNOG00000001442
drosophila_melanogaster	Cpr	FBGN0015623
caenorhabditis_elegans		WBGENE00001262

Paralogs (5): NOS2 (ENSG00000007171), NOS1 (ENSG00000089250), MTRR (ENSG00000124275), NOS3 (ENSG00000164867), NDOR1 (ENSG00000188566)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97744) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 55 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating cholesterol level	4
pale liver	2
decreased body weight	2
hepatic steatosis	2
increased circulating testosterone level	2
decreased heart weight	2
decreased kidney weight	2
abnormal enzyme/coenzyme activity	2
abnormal xenobiotic pharmacokinetics	2
absent trabeculae carneae	1
short tail	1
abnormal liver morphology	1
enlarged liver	1
exencephaly	1
incomplete rostral neuropore closure	1
hepatic necrosis	1
abnormal embryo development	1
pericardial edema	1
intracranial hemorrhage	1
reduced fertility	1
reduced female fertility	1
female infertility	1
decreased litter size	1
abnormal embryonic tissue morphology	1
abnormal eye morphology	1

+30 more (showing top 25).

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
Yersinia pestis Pestoides F	A4TPY5	100.0%	Diamond
Escherichia coli O139:H28 str. E24377A	A7ZQK7	100.0%	Diamond
Escherichia coli ATCC 8739	B1IU77	100.0%	Diamond
Yersinia pestis Antiqua	Q1C3Z0	100.0%	Diamond
Yersinia pestis Nepal516	Q1CLS8	100.0%	Diamond
Yersinia pestis	Q8ZBN6	100.0%	Diamond
Escherichia coli K-12	P38038	99.8%	Diamond
Shigella boydii Sb227	Q31XM4	99.8%	Diamond
Vibrio vulnificus YJ016	Q7MHA5	99.8%	Diamond
Vibrio vulnificus CMCP6	Q8DCK2	99.8%	Diamond
Vibrio cholerae O395	A5F3I4	99.7%	Diamond
Yersinia pseudotuberculosis IP 31758	A7FLZ0	99.7%	Diamond
Vibrio cholerae O1 biovar El Tor str. N16961	Q9KUX4	99.7%	Diamond
Yersinia pseudotuberculosis IP 32953	Q66ED4	98.9%	Diamond
Aspergillus niger CBS 513.88	A2QS05	98.8%	Diamond
Aspergillus niger	Q00141	98.8%	Diamond
Salmonella enterica subsp. enterica serovar Paratyphi B str. SPB7	A9N2E6	98.5%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	P38039	98.5%	Diamond
Shewanella sp. MR-4	Q0HFL6	98.5%	Diamond
Shewanella sp. MR-7	Q0HYB4	98.5%	Diamond
Shewanella sp. ANA-3	A0KTH4	98.2%	Diamond
Pongo abelii	Q5REF9	98.0%	Diamond
Salmonella enterica subsp. enterica serovar Choleraesuis str. SC-B67	Q57KH7	97.8%	Diamond
Salmonella enterica subsp. enterica serovar Paratyphi A str. ATCC 9150	Q5PEH7	97.8%	Diamond
Salmonella enterica subsp. enterica serovar Typhi	Q8Z458	97.8%	Diamond
Bos taurus	Q27995	97.0%	Diamond
Capra hircus	Q28314	97.0%	Diamond
Oryctolagus cuniculus	O19114	95.4%	Diamond
Canis lupus familiaris	Q9TUX8	93.5%	Diamond
Sus scrofa	P04175	92.9%	Diamond
Sorghum bicolor	C5YJG8	92.8%	Diamond
Oryza sativa Japonica Group	Q0J705	92.8%	Diamond
Cavia porcellus	P37039	92.0%	Diamond
Ovis aries	Q29498	91.9%	Diamond
Aspergillus oryzae RIB40	Q2UHA7	91.7%	Diamond
Aspergillus terreus NIH2624	Q0CMM0	91.2%	Diamond
Aspergillus nidulans FGSC A4	Q5BFT5	90.9%	Diamond
Klebsiella pneumoniae subsp. pneumoniae MGH 78578	A6TD49	90.7%	Diamond
Yersinia enterocolitica subsp. enterocolitica 8081	A1JJS2	89.7%	Diamond
Aspergillus fumigatus Af293	Q4WM67	89.1%	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
MIR4651	ncRNA	100616270
SNORA14A	snoRNA	677801
TMEM120A	protein-coding	83862
RHBDD2	protein-coding	57414
STYXL1	protein-coding	51657
MDH2	protein-coding	4191
CCL24	protein-coding	6369

Protein

Protein identifiers

NADPH–cytochrome P450 reductase — P16435 (reviewed: P16435)

All UniProt accessions (19): P16435, A0A8V8NE24, A0A8V8NKH1, A0A8V8NLF0, A0A8V8NRY5, A0A8V8NVX2, A0A8V8NVY2, A0A8V8P1G2, A0A8V8P672, A0A8V8PBF2, A0A9L9PXL8, A0A9L9PXN4, A0A9L9PY49, C9JDE2, C9JQ78, C9JU80, E7EMD0, E7EWU0, H0Y4R2

UniProt curated annotations — full annotation on UniProt →

Function. This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Antley-Bixler syndrome, with genital anomalies and disordered steroidogenesis (ABS1) [MIM:201750] A disease characterized by the association of Antley-Bixler syndrome with steroidogenesis defects and abnormal genitalia. Antley-Bixler syndrome is characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures. The disease is caused by variants affecting the gene represented in this entry. Disordered steroidogenesis due to cytochrome P450 oxidoreductase deficiency (DISPORD) [MIM:613571] A disorder resulting in a rare variant of congenital adrenal hyperplasia, with apparent combined P450C17 and P450C21 deficiency and accumulation of steroid metabolites. Affected girls are born with ambiguous genitalia, but their circulating androgens are low and virilization does not progress. Conversely, affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, in some cases resembling the pattern seen in patients with Antley-Bixler syndrome. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 FAD per monomer. Binds 1 FMN per monomer.

Similarity. Belongs to the NADPH–cytochrome P450 reductase family. In the N-terminal section; belongs to the flavodoxin family. In the C-terminal section; belongs to the flavoprotein pyridine nucleotide cytochrome reductase family.

RefSeq proteins (7): NP_001354491, NP_001369584, NP_001369586, NP_001369587, NP_001369588, NP_001369591, NP_001382342* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001094	Flavdoxin-like	Domain
IPR001433	OxRdtase_FAD/NAD-bd	Domain
IPR001709	Flavoprot_Pyr_Nucl_cyt_Rdtase	Domain
IPR003097	CysJ-like_FAD-binding	Domain
IPR008254	Flavodoxin/NO_synth	Domain
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR023173	NADPH_Cyt_P450_Rdtase_alpha	Homologous_superfamily
IPR023208	P450R	Family
IPR029039	Flavoprotein-like_sf	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily

Pfam: PF00175, PF00258, PF00667

Enzyme classification (BRENDA)

• EC 1.6.2.4 — NADPH-hemoprotein reductase (BRENDA: 126 organisms, 159 substrates, 73 inhibitors, 211 Km, 121 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
NADPH	—	79
FERRICYTOCHROME C	0.0009–0.0924	48
CYTOCHROME C	—	32
OXIDIZED 3-(4,5-DIMETHYLTHIAZOL-2-YL)-2,5-DIPHEN	0.0018–0.011	15
NADH	0.0084–50	11
FERRICYANIDE	0.0072–0.1193	3
4-NITROACETOPHENONE	1.4	2
OXIDIZED 2,6-DICHLOROPHENOLINDOPHENOL	0.055–0.077	2
4-NITROBENZALDEHYDE	0.31	1
5-CYANO-2,3-DITOLYL TETRAZOLIUM CHLORIDE	0.05	1
AZIDONITROPHENYL-GAMMA-AMINOBUTYRYL-NADPH	0.0019	1
BENZALACETONE	2.5	1
ETHANOL	7.2	1
HEXADECANAL	0.03	1
MENADIONE	0.0053	1

Catalyzed reactions (Rhea)

• 2 oxidized [cytochrome P450] + NADPH = 2 reduced [cytochrome P450] + NADP(+) + H(+) (RHEA:24040)

UniProt features (106 total): helix 31, strand 30, binding site 15, sequence variant 12, turn 6, sequence conflict 3, topological domain 2, modified residue 2, domain 2, initiator methionine 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

14 structures by resolution:

PDB	Title	Method	Resolution (Å)
9EB1	CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE (MUTANT …	X-RAY DIFFRACTION	1.1
9EB0	CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE (MUTANT …	X-RAY DIFFRACTION	1.13
9EAZ	CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE (MUTANT …	X-RAY DIFFRACTION	1.17
9EAX	CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE (MUTANT …	X-RAY DIFFRACTION	1.35
3QFS	Crystal Structure of NADPH-Cytochrome P450 Reductase (FAD/NADPH domain)	X-RAY DIFFRACTION	1.4
3QFT	Crystal Structure of NADPH-Cytochrome P450 Reductase (FAD/NADPH domain and R457H Mutant)	X-RAY DIFFRACTION	1.4
9EAY	CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE (MUTANT …	X-RAY DIFFRACTION	1.5
3QE2	Crystal Structure of Human NADPH-Cytochrome P450 Reductase	X-RAY DIFFRACTION	1.75
3QFC	Crystal Structure of Human NADPH-Cytochrome P450 (V492E mutant)	X-RAY DIFFRACTION	1.8
1B1C	CRYSTAL STRUCTURE OF THE FMN-BINDING DOMAIN OF HUMAN CYTOCHROME P450 REDUCTASE AT 1.93A …	X-RAY DIFFRACTION	1.93
5EMN	Crystal Structure of Human NADPH-Cytochrome P450 Reductase(A287P mutant)	X-RAY DIFFRACTION	2.2
5FA6	wild type human CYPOR	X-RAY DIFFRACTION	2.3
3QFR	Crystal Structure of Human NADPH-Cytochrome P450 Reductase (R457H Mutant)	X-RAY DIFFRACTION	2.4
3FJO	Structure of chimeric YH CPR	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16435-F1	91.29	0.81

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Transporters, Electrochemical Potential-driven transporters, Predicted membrane proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of skin

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH enhanced · 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.

Ligand- & substrate-binding residues (15)

Position	Role
208	FMN
298	NADP(+)
424	FAD
454–457	FAD
472–474	FAD
478	FAD
488–491	FAD
535	NADP(+)
596–597	NADP(+)
602–606	NADP(+)
638	NADP(+)
676	FAD
86–91	FMN
138–141	FMN
173–182	FMN

Post-translational modifications (2)

Type	Positions
N-acetylglycine	2
Phosphoserine	63

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-211897	Cytochrome P450 - arranged by substrate type	curated
R-HSA-211859	Biological oxidations	—
R-HSA-1430728	Metabolism	—
R-HSA-211945	Phase I - Functionalization of compounds	—

MSigDB gene sets: 0 (showing top):

GO Biological Process (21): nitric oxide biosynthetic process (GO:0006809), response to nutrient (GO:0007584), response to xenobiotic stimulus (GO:0009410), carnitine metabolic process (GO:0009437), response to hormone (GO:0009725), fatty acid oxidation (GO:0019395), electron transport chain (GO:0022900), positive regulation of chondrocyte differentiation (GO:0032332), negative regulation of apoptotic process (GO:0043066), nitrate catabolic process (GO:0043602), positive regulation of smoothened signaling pathway (GO:0045880), nitric oxide catabolic process (GO:0046210), positive regulation of growth plate cartilage chondrocyte proliferation (GO:0061913), demethylation (GO:0070988), cellular response to follicle-stimulating hormone stimulus (GO:0071372), cellular response to peptide hormone stimulus (GO:0071375), response to dexamethasone (GO:0071548), positive regulation of steroid hormone biosynthetic process (GO:0090031), organofluorine metabolic process (GO:0090346), P450-containing electron transport chain (GO:0140647), cellular response to gonadotropin stimulus (GO:0071371)

GO Molecular Function (13): NADPH-hemoprotein reductase activity (GO:0003958), cytochrome-b5 reductase activity, acting on NAD(P)H (GO:0004128), enzyme activator activity (GO:0008047), nitric oxide dioxygenase [NAD(P)H] activity (GO:0008941), electron transfer activity (GO:0009055), FMN binding (GO:0010181), hydrolase activity (GO:0016787), enzyme binding (GO:0019899), iron-cytochrome-c reductase activity (GO:0047726), flavin adenine dinucleotide binding (GO:0050660), NADP binding (GO:0050661), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (6): nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), intracellular membrane-bounded organelle (GO:0043231), cytoplasm (GO:0005737)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Phase I - Functionalization of compounds	1
Metabolism	1
Biological oxidations	1

GO top-level categories

60 GO namespaces:

Category	Terms
cellular anatomical structure	4
response to chemical	3
catalytic activity	3
nitric oxide metabolic process	2
catabolic process	2
oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor	2
anion binding	2
intracellular anatomical structure	2
biosynthetic process	1
response to nutrient levels	1
amino-acid betaine metabolic process	1
response to endogenous stimulus	1
fatty acid metabolic process	1
lipid oxidation	1
generation of precursor metabolites and energy	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
positive regulation of cell differentiation	1
positive regulation of cartilage development	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
nitrate metabolic process	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
growth plate cartilage chondrocyte proliferation	1
regulation of growth plate cartilage chondrocyte proliferation	1
positive regulation of cell population proliferation	1
metabolic process	1
response to follicle-stimulating hormone	1
cellular response to gonadotropin stimulus	1
cellular response to hormone stimulus	1
response to peptide hormone	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to glucocorticoid	1
response to ketone	1
positive regulation of steroid biosynthetic process	1
positive regulation of hormone biosynthetic process	1
regulation of steroid hormone biosynthetic process	1
organohalogen metabolic process	1
electron transport chain	1
enzyme regulator activity	1
molecular function activator activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of two atoms of oxygen into one donor	1
molecular_function	1
ribonucleotide binding	1
protein binding	1
oxidoreductase activity, acting on metal ions	1
nucleotide binding	1
adenyl nucleotide binding	1
binding	1
nuclear lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
membrane-bounded organelle	1
intracellular organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 40 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
electron transport chain	BP	direct assay
organofluorine metabolic process	BP	direct assay
cytosol	CC	direct assay
intracellular membrane-bounded organelle	CC	direct assay
membrane	CC	high-throughput assay
nucleoplasm	CC	direct assay
NADPH-hemoprotein reductase activity	MF	direct assay
enzyme activator activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,409 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POR	CYP51A1	Q16850	915
POR	CYB5A	P00167	850
POR	CYB5B	O43169	849
POR	CYP17A1	P05093	842
POR	CYP21A2	P04033	726
POR	PPIG	Q13427	715
POR	CYB5R1	Q9UHQ9	670
POR	CYP2B6	P20813	664
POR	CYP3A4	P05184	649
POR	CYB5R3	P00387	614
POR	CYB5RL	Q6IPT4	613
POR	CYP1A2	P05177	607
POR	FGFR2	P18443	597
POR	HSD3B2	P26439	594
POR	CYCS	P00001	584

IntAct

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

9 partners by confidence:

Partner	Interaction type	MIscore	Records
PGRMC1	physical association	0.680	4
SNX8	association	0.640	3
CYP2C2	physical association	0.580	3
CYCS	direct interaction	0.440	1
RABEPK	physical association	0.370	1
STAT1	physical association	0.370	1
UBXN6	association	0.350	2
MATN1	association	0.350	1
XRCC6	physical association	0.000	1

BioGRID (346 interactions; top human partners by supporting records): CYP2E1 (PCA; 4 records), UBXN6 (Affinity Capture-MS; 4 records), CYP1A2 (Reconstituted Complex; 3 records), CYP2C9 (Proximity Label-MS; 3 records), EMC4 (Co-fractionation; 3 records), FANCC (Affinity Capture-Western; 3 records), PGRMC1 (Affinity Capture-MS; 3 records), SEC61B (Proximity Label-MS; 3 records), BCAP31 (Proximity Label-MS; 2 records), CANX (Co-fractionation; 2 records), CYP2A6 (Reconstituted Complex; 2 records), CYP2C19 (Reconstituted Complex; 2 records), CYP2D6 (Reconstituted Complex; 2 records), CYP3A4 (Reconstituted Complex; 2 records), DERL1 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
SP1	“up-regulates quantity by expression”	POR	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for POR: 905 ClinVar records (93 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	34
Uncertain significance	242
Likely benign	430
Benign	31

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 93 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
16915	NM_001395413.1(POR):c.1606G>A (p.Gly536Arg)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
1405328	NM_001395413.1(POR):c.723-2A>T	Pathogenic	criteria provided, multiple submitters, no conflicts	5
580516	NM_001395413.1(POR):c.1562_1610dup (p.Ala538fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
691923	NM_001395413.1(POR):c.1434C>A (p.Tyr478Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2735033	NM_001395413.1(POR):c.658C>T (p.Arg220Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2919493	NM_001395413.1(POR):c.735C>G (p.Tyr245Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3594771	NM_001395413.1(POR):c.1718dup (p.Tyr573Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
16903	NM_001395413.1(POR):c.1697G>A (p.Cys566Tyr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
3339945	NM_001395413.1(POR):c.1685T>C (p.Leu562Pro)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
576622	NM_001395413.1(POR):c.179+2T>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2822770	NM_001395413.1(POR):c.1240-2A>G	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1684295	NM_001395413.1(POR):c.1166dup (p.Ala390fs)	Pathogenic	criteria provided, single submitter	1
2065334	NM_001395413.1(POR):c.1795C>T (p.Gln599Ter)	Pathogenic	criteria provided, single submitter	1
2695460	NM_001395413.1(POR):c.697del (p.Val233fs)	Pathogenic	criteria provided, single submitter	1
2707022	NM_001395413.1(POR):c.1631_1634del (p.Ile544fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore POR’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.

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.95e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	3.08e-05
Thyroid Carcinoma (TCGA)	unfavorable	0.000754

Disease associations

OMIM: gene MIM:124015 | disease phenotypes: MIM:201750, MIM:613571, MIM:207410, MIM:601353

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	Definitive	Autosomal recessive	3
congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	Strong	Autosomal recessive	3

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 11 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
Arthrogryposis	green
Differences in sex development	green
Fetal anomalies	green
Hypotonic infant	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Rare syndromic craniosynostosis or isolated multisuture synostosis	green
Skeletal dysplasia	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (5): Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MONDO:0008726), congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (MONDO:0013310), congenital adrenal hyperplasia (MONDO:0018479), Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis (MONDO:0020667), Fine-Lubinsky syndrome (MONDO:0011049)

Orphanet (6): Congenital adrenal hyperplasia (Orphanet:418), Antley-Bixler syndrome without genital anomaly or disorder of steroidogenesis (Orphanet:596008), Antley-Bixler syndrome with genital anomaly and disorder of steroidogenesis (Orphanet:63269), Antley-Bixler syndrome (Orphanet:83), Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (Orphanet:95699), Aymé-Gripp syndrome (Orphanet:1272)

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D000312	Adrenal Hyperplasia, Congenital	C12.050.351.875.253.090.500; C12.200.706.316.090.500; C12.800.316.090.500; C16.131.939.316.129.500; C16.320.033; C16.320.565.925.249; C18.452.648.925.249; C19.053.440; C19.391.119.090.500
C537933	Fine-Lubinsky syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2169731 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 606 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL15192	LAPACHONE	2	606

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

12 measured of 12 human assays (12 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM
R115 (Reactive Blue 2)	IC50	2100 nM
CHEMBL4102425	IC50	2400 nM
CHEMBL4074173	IC50	2900 nM
CHEMBL4086536	IC50	3100 nM
CHEMBL4065098	IC50	3100 nM
CHEMBL4094677	IC50	4100 nM
CHEMBL3398293	IC50	5800 nM
CHEMBL4080037	IC50	8500 nM
CHEMBL4098063	IC50	11000 nM
CHEMBL3398294	IC50	11000 nM
CHEMBL3398292	IC50	12000 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 13 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.20	IC50	6300	nM	CHEMBL4094677
5.05	IC50	9000	nM	CHEMBL4086536

PubChem BioAssay actives

2 with measured affinity, of 114 total; 2 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
3,8-dimethylbenzo[g][1]benzofuran-4,5-dione	1441532: Substrate activity at CPR in human L02 cells assessed as CPR-mediated one-electron reduction of compound by measuring cell growth inhibition treated for 24 hrs measured after 72 hrs by MTT assay	ic50	6.3000	uM
7,8-dimethylbenzo[g][1]benzofuran-4,5-dione	1441532: Substrate activity at CPR in human L02 cells assessed as CPR-mediated one-electron reduction of compound by measuring cell growth inhibition treated for 24 hrs measured after 72 hrs by MTT assay	ic50	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects binding, increases reaction, decreases expression, decreases methylation (+1 more)	7
perfluorooctanoic acid	affects cotreatment, increases expression	5
perfluorooctane sulfonic acid	affects expression, affects cotreatment, increases expression	5
NADP	affects cotreatment, increases oxidation, affects reaction, increases activity, increases chemical synthesis (+4 more)	5
Aflatoxin B1	affects expression, decreases expression, increases methylation, affects cotreatment, increases response to substance	5
Benzo(a)pyrene	increases mutagenesis, increases response to substance, decreases expression, decreases methylation, affects cotreatment	4
Hydrogen Peroxide	increases abundance, increases metabolic processing, affects cotreatment, increases chemical synthesis, increases reaction (+1 more)	4
Paraquat	increases chemical synthesis, increases response to substance, decreases reaction, increases abundance, increases metabolic processing (+3 more)	4
Phenobarbital	affects expression, increases expression	4
Cadmium Chloride	increases activity, increases expression, decreases reaction	4
diphenyleneiodonium	increases activity, increases abundance, increases metabolic processing, decreases activity, decreases reaction	3
sodium arsenite	decreases expression, increases expression	3
perfluoro-n-nonanoic acid	affects cotreatment, increases expression	3
Doxorubicin	decreases expression, decreases response to substance, affects metabolic processing, increases activity	3
Quercetin	decreases activity, increases activity, affects cotreatment, decreases reaction, increases metabolic processing	3
Tretinoin	increases expression	3
aristolochic acid I	increases expression, increases metabolic processing	2
dibutylnitrosamine	affects cotreatment, increases response to substance	2
N-nitroso(di-n-propyl)amine	affects cotreatment, increases response to substance	2
sulforaphane	affects cotreatment, increases expression	2
2-amino-3-methylimidazo(4,5-f)quinoline	affects cotreatment, increases response to substance	2
2-amino-3,4-dimethylimidazo(4,5-f)quinoline	affects cotreatment, increases response to substance	2
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	affects cotreatment, increases response to substance	2
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	affects cotreatment, increases response to substance	2
2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone	increases reduction, increases activity	2
perfluorohexanesulfonic acid	increases expression, affects cotreatment	2
perfluorohexanoic acid	increases expression	2
Troglitazone	increases expression	2
Air Pollutants	increases oxidation, increases expression, affects cotreatment, increases abundance	2
Cyclophosphamide	increases response to substance, increases reaction	2

ChEMBL screening assays

21 unique, capped per target: 14 admet, 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2175347	Binding	Activity of human recombinant cytochrome P450 reductase assessed as rate of superoxide generation measuring SOD-inhibitable reduction of succinoylated cytochrome c per 2 mU enzyme at 100 umol/ml by spectrophotometry in presence of catalase	Synthesis and structure-activity relationships of lapacho analogues. 1. Suppression of human keratinocyte hyperproliferation by 2-substituted naphtho[2,3-b]furan-4,9-diones, activation by enzymatic one- and two-electron reduction, and intracellular generation of superoxide. — *J Med Chem*
CHEMBL4009115	ADMET	Substrate activity at CPR in human L02 cells assessed as CPR-mediated one-electron reduction of compound by measuring ROS production at 10 uM after 1 to 3 hrs by DCFH-DA staining based flow cytometry	Discovery of quinone-directed antitumor agents selectively bioactivated by NQO1 over CPR with improved safety profile. — *Eur J Med Chem*

Cellosaurus cell lines

22 cell lines: 10 spontaneously immortalized cell line, 7 cancer cell line, 4 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A4XZ	WMUi018-A	Induced pluripotent stem cell	Female
CVCL_A9XC	BGUi001-A	Induced pluripotent stem cell	Male
CVCL_A9XD	BGUi002-A	Induced pluripotent stem cell	Male
CVCL_A9XE	BGUi003-A	Induced pluripotent stem cell	Male
CVCL_B1E1	Abcam HCT 116 POR KO	Cancer cell line	Male
CVCL_B2BK	Abcam HeLa POR KO	Cancer cell line	Female
CVCL_B5WP	V79MZh1B1	Spontaneously immortalized cell line	Male
CVCL_B6AR	HepaRG POR KO	Cancer cell line	Female
CVCL_C0R0	HepaRG-POR#1	Cancer cell line	Female
CVCL_C0R1	HepaRG-POR#2	Cancer cell line	Female

Clinical trials (associated diseases)

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

showing 60 of 215 trials:

NCT	Phase	Status	Title
NCT03760835	Phase 4	RECRUITING	Congenital Adrenal Hyperplasia Once Daily Hydrocortisone Treatment
NCT04536662	Phase 4	UNKNOWN	Comparisons of Different Forms of Glucocorticoid on the Recovery of Reproductive Function in Patients With 21α-hydroxylase Deficiency
NCT02343562	Phase 4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	Phase 4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT00417066	Phase 4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	Phase 4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	Phase 4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	Phase 4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	Phase 4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	Phase 4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00001521	Phase 3	COMPLETED	Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia
NCT02716818	Phase 3	COMPLETED	Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia
NCT03062280	Phase 3	COMPLETED	A Study of the Efficacy, Safety and Tolerability of Chronocort in Treating CAH
NCT03532022	Phase 3	WITHDRAWN	Open-label Comparison of Chronocort® Versus Standard Glucocorticoid Replacement Therapy
NCT04490915	Phase 3	ACTIVE_NOT_RECRUITING	Global Safety and Efficacy Registration Study of Crinecerfont for Congenital Adrenal Hyperplasia
NCT04806451	Phase 3	ACTIVE_NOT_RECRUITING	Global Safety and Efficacy Registration Study of Crinecerfont in Pediatric Participants With Classic Congenital Adrenal Hyperplasia (CAHtalyst Pediatric Study)
NCT05063994	Phase 3	COMPLETED	Comparison of Chronocort Versus Standard Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia
NCT05299554	Phase 3	COMPLETED	Long-term Safety Study of Chronocort in the Treatment of Participants With Congenital Adrenal Hyperplasia
NCT07144163	Phase 3	RECRUITING	A Study to Evaluate Atumelnant in Adults With Congenital Adrenal Hyperplasia
NCT03660176	Phase 3	NOT_YET_RECRUITING	Effects of Butyrate Enemas on Postoperative Intestinal Motility Disorders in Hirschsprung’s Disease
NCT04904081	Phase 3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00140998	Phase 3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00621985	Phase 2	COMPLETED	Dexamethasone Treatment of Congenital Adrenal Hyperplasia
NCT01735617	Phase 2	COMPLETED	Pilot Study to Characterize and Examine the Pharmacokinetics and Efficacy of Chronocort® in Adults With CAH
NCT01771328	Phase 2	UNKNOWN	Continuous Subcutaneous Hydrocortisone Infusion in Congenital Adrenal Hyperplasia
NCT01859312	Phase 2	COMPLETED	Comparison of Cortisol Pump With Standard Treatment for Congenital Adrenal Hyperplasia
NCT02804178	Phase 2	COMPLETED	A Study of ATR-101 for the Treatment of Congenital Adrenal Hyperplasia
NCT03257462	Phase 2	COMPLETED	Study of SPR001 in Adults With Classic Congenital Adrenal Hyperplasia
NCT03548246	Phase 2	WITHDRAWN	Androgen Reduction in Congenital Adrenal Hyperplasia
NCT03669549	Phase 2	TERMINATED	Nevanimibe HCl for the Treatment of Classic CAH
NCT03687242	Phase 2	COMPLETED	Study to Evaluate the Safety and Efficacy of SPR001 in Subjects With Classic Congenital Adrenal Hyperplasia
NCT04457336	Phase 2	TERMINATED	A Ph2b to Evaluate Clinical Efficacy and Safety of Tildacerfont in Adult CAH
NCT04544410	Phase 2	TERMINATED	A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH
NCT05128942	Phase 2	TERMINATED	A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children Aged 2-17 Years With CAH
NCT05907291	Phase 2	COMPLETED	Evaluate the Safety, Efficacy, and Pharmacokinetics of CRN04894 in Participants With Congenital Adrenal Hyperplasia (TouCAHn)
NCT06712823	Phase 2	RECRUITING	An Extension Study to Evaluate Safety and Efficacy of Atumelnant in Participants With Congenital Adrenal Hyperplasia
NCT07187375	Phase 2	ACTIVE_NOT_RECRUITING	Pharmacokinetics, Safety and Tolerability of Crinecerfont in Participants With Congenital Adrenal Hyperplasia Who Are Less Than 2 Years Old
NCT07536269	Phase 2	RECRUITING	Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Crinecerfont in Participants With Classic Congenital Adrenal Hyperplasia (CAH) Who Are Less Than 4 Years Old
NCT00630838	Phase 2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT00001951	Phase 2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	Phase 2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	Phase 2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	Phase 2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	Phase 2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	Phase 2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02349503	Phase 1	WITHDRAWN	Safety, Pharmacokinetics and Pharmacodynamics of NBI-77860 in Adolescent Females With Congenital Adrenal Hyperplasia
NCT02574910	Phase 1	TERMINATED	Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1
NCT03019614	Phase 1	COMPLETED	An Open Label Study in Healthy Volunteers to Compare Chronocort® to Hydrocortisone
NCT03051893	Phase 1	COMPLETED	A Two-part, Study to Compare the Pharmacokinetics and Dose Proportionality of up to 6 Chronocort Formulations
NCT03718234	Phase 1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT07811089	Phase 1	NOT_YET_RECRUITING	Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of OMS1620
NCT02912104	Phase 1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	Phase 1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	Phase 1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	Phase 1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	Phase 1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT02552251	Phase 2/3	UNKNOWN	COrticosteroid in Congenital Adrenal Hyperplasia
NCT07159841	Phase 2/3	RECRUITING	A Study in Pediatric Participants With Congenital Adrenal Hyperplasia (Balance-CAH)
NCT00000102	Phase 1/2	COMPLETED	Congenital Adrenal Hyperplasia: Calcium Channels as Therapeutic Targets
NCT00519818	Phase 1/2	COMPLETED	Comparison of Two Forms of Hydrocortisone in Patients With Congenital Adrenal Hyperplasia

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for POR across ~30M SureChEMBL compounds — explore on Sugi Predict.