CYB5R1

Summary

CYB5R1 (cytochrome b5 reductase 1, HGNC:13397) is a protein-coding gene on chromosome 1q32.1, encoding NADH-cytochrome b5 reductase 1 (Q9UHQ9). NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.

Predicted to enable FAD binding activity. Predicted to be involved in bicarbonate transport. Located in cytosol and mitochondrion.

Source: NCBI Gene 51706 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_016243

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13397
Approved symbol	CYB5R1
Name	cytochrome b5 reductase 1
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	humb5R2
Ensembl gene	ENSG00000159348
Ensembl biotype	protein_coding
OMIM	608341
Entrez	51706

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000367249, ENST00000446185, ENST00000473599, ENST00000478009, ENST00000482572, ENST00000483915, ENST00000497655, ENST00000893435, ENST00000893436, ENST00000893437, ENST00000893438, ENST00000919125, ENST00000919126, ENST00000919127, ENST00000919128, ENST00000964626, ENST00000964627

RefSeq mRNA: 1 — MANE Select: NM_016243 NM_016243

CCDS: CCDS1431

Canonical transcript exons

ENST00000367249 — 9 exons

Exon	Start	End
ENSE00001443927	202961873	202962699
ENSE00001933185	202967191	202967257
ENSE00003496923	202965371	202965500
ENSE00003541448	202964612	202964695
ENSE00003560906	202966528	202966600
ENSE00003567443	202966749	202966898
ENSE00003571255	202963066	202963165
ENSE00003584184	202965887	202965993
ENSE00003672348	202963642	202963727

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.3581 / max 724.2977, expressed in 1820 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16760	30.4914	1820
16761	1.2722	951
201881	0.5945	261

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.22	gold quality
gastrocnemius	UBERON:0001388	99.17	gold quality
gluteal muscle	UBERON:0002000	99.05	gold quality
biceps brachii	UBERON:0001507	98.96	gold quality
muscle of leg	UBERON:0001383	98.92	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.92	gold quality
skeletal muscle tissue	UBERON:0001134	98.87	gold quality
muscle organ	UBERON:0001630	98.87	gold quality
deltoid	UBERON:0001476	98.73	gold quality
vastus lateralis	UBERON:0001379	98.66	gold quality
quadriceps femoris	UBERON:0001377	98.60	gold quality
body of tongue	UBERON:0011876	98.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.58	gold quality
triceps brachii	UBERON:0001509	98.55	gold quality
tibialis anterior	UBERON:0001385	98.35	gold quality
diaphragm	UBERON:0001103	98.25	gold quality
skin of abdomen	UBERON:0001416	97.96	gold quality
muscle tissue	UBERON:0002385	97.91	gold quality
apex of heart	UBERON:0002098	97.82	gold quality
skin of leg	UBERON:0001511	97.79	gold quality
heart left ventricle	UBERON:0002084	97.79	gold quality
cardiac ventricle	UBERON:0002082	97.77	gold quality
right uterine tube	UBERON:0001302	97.66	gold quality
dorsal root ganglion	UBERON:0000044	97.55	gold quality
zone of skin	UBERON:0000014	97.37	gold quality
heart right ventricle	UBERON:0002080	97.27	gold quality
body of stomach	UBERON:0001161	97.16	gold quality
heart	UBERON:0000948	96.76	gold quality
tongue	UBERON:0001723	96.55	gold quality
corpus epididymis	UBERON:0004359	96.53	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	94.05
E-MTAB-6701	yes	42.52
E-CURD-114	yes	12.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting CYB5R1, 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-6721-5P	99.93	68.92	2981
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-1301-5P	98.09	66.62	495
HSA-MIR-6502-5P	98.09	66.73	495
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-1278	97.75	67.55	628
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-550B-3P	95.43	67.73	599
HSA-MIR-6889-5P	90.26	64.13	291
HSA-MIR-6777-5P	88.76	62.64	222

Literature-anchored findings (GeneRIF, showing 3)

• Data show that cytochrome b5 reductase 1 (CYB5R1) gene expression is strongly linked to epithelial-mesenchymal transition (EMT) in colon cancer. (PMID:27120783)
• Microsomal reductase activity in patients with thyroid neoplasms. (PMID:33011882)
• Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1. (PMID:33321093)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cyb5r1	ENSMUSG00000026456
rattus_norvegicus	Cyb5r1	ENSRNOG00000003973

Paralogs (5): CYB5R4 (ENSG00000065615), CYB5R3 (ENSG00000100243), OXNAD1 (ENSG00000154814), CYB5R2 (ENSG00000166394), CYB5RL (ENSG00000215883)

Protein

Protein identifiers

NADH-cytochrome b5 reductase 1 — Q9UHQ9 (reviewed: Q9UHQ9)

Alternative names: Humb5R2, NAD(P)H:quinone oxidoreductase type 3 polypeptide A2

All UniProt accessions (2): Q9UHQ9, H7C0R7

UniProt curated annotations — full annotation on UniProt →

Function. NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.

Subcellular location. Membrane.

Tissue specificity. Widely expressed.

Similarity. Belongs to the flavoprotein pyridine nucleotide cytochrome reductase family.

RefSeq proteins (1): NP_057327* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001433	OxRdtase_FAD/NAD-bd	Domain
IPR001709	Flavoprot_Pyr_Nucl_cyt_Rdtase	Domain
IPR001834	CBR-like	Family
IPR008333	Cbr1-like_FAD-bd_dom	Domain
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily

Pfam: PF00175, PF00970

Catalyzed reactions (Rhea), 1 shown:

• 2 Fe(III)-[cytochrome b5] + NADH = 2 Fe(II)-[cytochrome b5] + NAD(+) + H(+) (RHEA:46680)

UniProt features (10 total): sequence conflict 4, binding site 2, chain 1, transmembrane region 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHQ9-F1	94.56	0.89

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 (2): 136–166; 175–210

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-1237044	Erythrocytes take up carbon dioxide and release oxygen
R-HSA-109582	Hemostasis
R-HSA-1480926	O2/CO2 exchange in erythrocytes
R-HSA-382551	Transport of small molecules
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 206 (showing top): GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MODULE_66, GERY_CEBP_TARGETS, GOBP_STEROID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_BICARBONATE_TRANSPORT, BASSO_HAIRY_CELL_LEUKEMIA_UP, GOBP_LIPID_METABOLIC_PROCESS, MODULE_88, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_NAD_P_H

GO Biological Process (5): bicarbonate transport (GO:0015701), sterol biosynthetic process (GO:0016126), lipid metabolic process (GO:0006629), steroid biosynthetic process (GO:0006694), steroid metabolic process (GO:0008202)

GO Molecular Function (5): cytochrome-b5 reductase activity, acting on NAD(P)H (GO:0004128), FAD binding (GO:0071949), cytochrome-b5 reductase activity, acting on NADH (GO:0090524), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (7): mitochondrion (GO:0005739), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), platelet alpha granule membrane (GO:0031092), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
O2/CO2 exchange in erythrocytes	1
Transport of small molecules	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
transport	1
steroid biosynthetic process	1
sterol metabolic process	1
primary metabolic process	1
steroid metabolic process	1
lipid biosynthetic process	1
lipid metabolic process	1
oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor	1
flavin adenine dinucleotide binding	1
cytochrome-b5 reductase activity, acting on NAD(P)H	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
secretory granule membrane	1
platelet alpha granule	1
extracellular vesicle	1

Protein interactions and networks

STRING

1528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYB5R1	CYB5B	O43169	993
CYB5R1	CYB5A	P00167	993
CYB5R1	SCD	O00767	818
CYB5R1	POR	P16435	672
CYB5R1	CYP51A1	Q16850	570
CYB5R1	DHODH	Q02127	528
CYB5R1	SUOX	P51687	471
CYB5R1	CYCS	P00001	433
CYB5R1	CYP11A1	P05108	426
CYB5R1	FDXR	P22570	423
CYB5R1	NQO1	P15559	420
CYB5R1	CYP27C1	Q4G0S4	410
CYB5R1	AIFM2	Q9BRQ8	409
CYB5R1	G6PD	P11413	388
CYB5R1	CYP4F8	P98187	385

IntAct

125 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
UBQLN1	CYB5R1	psi-mi:“MI:0915”(physical association)	0.560
CYB5R1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
HIGD1C	CYB5R1	psi-mi:“MI:0915”(physical association)	0.560
TTC1	CYB5R1	psi-mi:“MI:0915”(physical association)	0.560
SGTB	CYB5R1	psi-mi:“MI:0915”(physical association)	0.560
SGTA	CYB5R1	psi-mi:“MI:0915”(physical association)	0.560
SLC51B	CYB5R1	psi-mi:“MI:0915”(physical association)	0.560
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC7A1	TMEM223	psi-mi:“MI:0914”(association)	0.530
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
IL20RA	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
BTNL3	FAM171A2	psi-mi:“MI:0914”(association)	0.530
MFSD8	FAM241A	psi-mi:“MI:0914”(association)	0.530
SFXN5	TOMM40	psi-mi:“MI:0914”(association)	0.530
CCT8L2	ACSL4	psi-mi:“MI:0914”(association)	0.530

BioGRID (158): CYB5R1 (Two-hybrid), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Co-fractionation), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS)

ESM2 similar proteins: A2AV36, A3KP77, A4IHY0, A8E7D2, B1AS42, D3ZG52, P00387, P17571, P20070, P32232, P35520, Q05B89, Q07G10, Q0CT94, Q13057, Q2UM43, Q3UZW7, Q4V7D6, Q4WN24, Q502I6, Q58DM7, Q58E95, Q58H57, Q5B5L3, Q5EB81, Q5R4D2, Q5RCH4, Q5U378, Q60HG4, Q6ING7, Q6IPT4, Q6JQN1, Q6ZQJ5, Q7T0L7, Q7T0X7, Q7T291, Q7ZW24, Q8AWD2, Q8K4Z3, Q8VE38

Diamond homologs: A0A286R227, A1C7E9, A1DHW1, A2QCV4, A3GF86, A3LT66, A4QR21, A4R935, A5DQ25, A5E7U2, A6R2K7, A6ZVM6, A7TNL7, B0CQN7, O74557, P00387, P07514, P07850, P08509, P08619, P0CP14, P0CP15, P11035, P11605, P11832, P16081, P17569, P17570, P17571, P20070, P22945, P23312, P27783, P27967, P27968, P27969, P36841, P36842, P36858, P36859

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 131 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Downstream signal transduction	5	24.4×	1e-04
FCERI mediated MAPK activation	5	22.2×	1e-04
Neurotransmitter receptors and postsynaptic signal transmission	6	7.7×	2e-03
Transmission across Chemical Synapses	7	6.8×	1e-03
Neuronal System	9	5.1×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transmembrane transport	8	15.0×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1023 predictions. Top by Δscore:

Variant	Effect	Δscore
1:202963060:GGATA:G	donor_loss	1.0000
1:202963061:GATAC:G	donor_loss	1.0000
1:202963062:ATAC:A	donor_loss	1.0000
1:202963063:TA:T	donor_loss	1.0000
1:202963065:C:CT	donor_loss	1.0000
1:202963162:CTGT:C	acceptor_gain	1.0000
1:202963163:TGT:T	acceptor_gain	1.0000
1:202963164:GT:G	acceptor_gain	1.0000
1:202963166:C:CC	acceptor_gain	1.0000
1:202963171:A:AC	acceptor_gain	1.0000
1:202963171:A:C	acceptor_gain	1.0000
1:202963174:C:CT	acceptor_gain	1.0000
1:202963638:CAAC:C	donor_loss	1.0000
1:202963639:AACCT:A	donor_loss	1.0000
1:202963640:ACCT:A	donor_loss	1.0000
1:202965365:CATTA:C	donor_loss	1.0000
1:202965366:ATTAC:A	donor_loss	1.0000
1:202965367:TTA:T	donor_loss	1.0000
1:202965368:TACCT:T	donor_loss	1.0000
1:202965369:ACCTT:A	donor_loss	1.0000
1:202965370:C:CT	donor_loss	1.0000
1:202966745:TTA:T	donor_loss	1.0000
1:202966746:TA:T	donor_loss	1.0000
1:202966747:A:AC	donor_gain	1.0000
1:202966747:AC:A	donor_gain	1.0000
1:202966748:C:CC	donor_gain	1.0000
1:202966748:C:CT	donor_loss	1.0000
1:202966748:CC:C	donor_gain	1.0000
1:202966748:CCGT:C	donor_gain	1.0000
1:202963175:A:T	acceptor_gain	0.9900

AlphaMissense

1957 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:202966569:A:G	F66S	0.995
1:202965403:C:T	G148E	0.994
1:202965897:A:G	L112P	0.994
1:202965933:G:T	P100H	0.994
1:202965404:C:G	G148R	0.993
1:202965404:C:T	G148R	0.993
1:202965406:C:G	R147P	0.993
1:202965471:A:C	F125L	0.993
1:202965471:A:T	F125L	0.993
1:202965473:A:G	F125L	0.993
1:202966572:C:G	R65P	0.992
1:202966568:A:C	F66L	0.991
1:202966568:A:T	F66L	0.991
1:202966570:A:G	F66L	0.991
1:202966575:A:G	F64S	0.991
1:202964623:G:T	A183D	0.990
1:202965451:G:A	S132F	0.990
1:202965945:C:A	R96M	0.990
1:202965404:C:A	G148W	0.989
1:202965945:C:G	R96T	0.989
1:202962612:C:T	C278Y	0.988
1:202963727:C:T	G187E	0.988
1:202965394:C:T	G151E	0.987
1:202962609:C:T	G279E	0.986
1:202962611:A:C	C278W	0.986
1:202962613:A:G	C278R	0.986
1:202963658:A:G	L210P	0.986
1:202965887:C:A	K115N	0.986
1:202965887:C:G	K115N	0.986
1:202965933:G:C	P100R	0.986

dbSNP variants (sampled 300 via entrez): RS1000341901 (1:202969045 C>G,T), RS1000758907 (1:202968774 A>T), RS1000826521 (1:202967018 G>A), RS1001107105 (1:202962214 T>C), RS1003531737 (1:202966954 G>A,C), RS1004385055 (1:202967660 C>T), RS1004465991 (1:202962837 C>T), RS1004902345 (1:202967980 G>A), RS1005357695 (1:202968340 A>G), RS1005471709 (1:202967878 C>T), RS1005500023 (1:202966499 G>A), RS1006352097 (1:202966681 G>A), RS1006470067 (1:202966448 A>C,T), RS1006702832 (1:202967057 G>A,C), RS1007708779 (1:202965631 T>G)

Disease associations

OMIM: gene MIM:608341 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	4
Valproic Acid	affects cotreatment, increases expression, increases methylation	4
bisphenol F	affects cotreatment, increases expression	2
cobaltous chloride	increases expression	2
Acetaminophen	affects response to substance, increases expression	2
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
GSK-J4	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
propionaldehyde	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
trichostatin A	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
motexafin gadolinium	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Bortezomib	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

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