CYB5A

Summary

CYB5A (cytochrome b5 type A, HGNC:2570) is a protein-coding gene on chromosome 18q22.3, encoding Cytochrome b5 (P00167). Cytochrome b5 is a membrane-bound hemoprotein functioning as an electron carrier for several membrane-bound oxygenases.

The protein encoded by this gene is a membrane-bound cytochrome that reduces ferric hemoglobin (methemoglobin) to ferrous hemoglobin, which is required for stearyl-CoA-desaturase activity. Defects in this gene are a cause of type IV hereditary methemoglobinemia. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1528 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methemoglobinemia type 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 35 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_148923

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2570
Approved symbol	CYB5A
Name	cytochrome b5 type A
Location	18q22.3
Locus type	gene with protein product
Status	Approved
Aliases	MCB5
Ensembl gene	ENSG00000166347
Ensembl biotype	protein_coding
OMIM	613218
Entrez	1528

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000299438, ENST00000340533, ENST00000397914, ENST00000494131, ENST00000579064, ENST00000580678, ENST00000583418, ENST00000886098, ENST00000886099, ENST00000886100, ENST00000886101, ENST00000886102, ENST00000918054, ENST00000918055

RefSeq mRNA: 3 — MANE Select: NM_148923 NM_001190807, NM_001914, NM_148923

CCDS: CCDS12004, CCDS12005, CCDS54188

Canonical transcript exons

ENST00000340533 — 5 exons

Exon	Start	End
ENSE00001878979	74291747	74291963
ENSE00003545546	74255741	74255775
ENSE00003585275	74263349	74263477
ENSE00003610820	74260915	74260944
ENSE00003736132	74250846	74253665

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.8928 / max 1853.4333, expressed in 1747 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172421	44.4901	1746
172420	1.8583	678
172422	0.4196	201
172419	0.1247	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nephron tubule	UBERON:0001231	99.74	gold quality
right lobe of liver	UBERON:0001114	99.69	gold quality
kidney epithelium	UBERON:0004819	99.54	gold quality
adult mammalian kidney	UBERON:0000082	99.53	gold quality
liver	UBERON:0002107	99.52	gold quality
renal medulla	UBERON:0000362	99.43	gold quality
renal glomerulus	UBERON:0000074	99.42	gold quality
pancreatic ductal cell	CL:0002079	99.41	gold quality
jejunal mucosa	UBERON:0000399	99.37	gold quality
metanephric glomerulus	UBERON:0004736	99.36	gold quality
body of pancreas	UBERON:0001150	99.33	gold quality
gall bladder	UBERON:0002110	99.27	gold quality
duodenum	UBERON:0002114	99.20	gold quality
right lung	UBERON:0002167	99.18	gold quality
bronchial epithelial cell	CL:0002328	99.14	gold quality
kidney	UBERON:0002113	99.13	gold quality
adult organism	UBERON:0007023	99.12	gold quality
metanephros cortex	UBERON:0010533	99.11	gold quality
upper leg skin	UBERON:0004262	99.07	gold quality
epithelium of bronchus	UBERON:0002031	99.04	gold quality
metanephros	UBERON:0000081	99.00	gold quality
bronchus	UBERON:0002185	98.99	gold quality
upper lobe of left lung	UBERON:0008952	98.95	gold quality
upper lobe of lung	UBERON:0008948	98.92	gold quality
left ovary	UBERON:0002119	98.74	gold quality
lung	UBERON:0002048	98.72	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.71	gold quality
right ovary	UBERON:0002118	98.67	gold quality
adipose tissue	UBERON:0001013	98.62	gold quality
cortex of kidney	UBERON:0001225	98.61	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-MTAB-8495	yes	4075.12
E-HCAD-15	yes	3831.07
E-MTAB-10553	yes	3153.19
E-CURD-122	yes	2988.46
E-GEOD-130148	yes	2791.30
E-MTAB-6653	yes	2621.55
E-HCAD-9	yes	2483.20
E-MTAB-8221	yes	2189.31
E-GEOD-114530	yes	2153.62
E-HCAD-1	yes	2107.46
E-CURD-126	yes	1975.29
E-MTAB-10662	yes	1686.47
E-MTAB-6308	yes	1637.04
E-MTAB-9388	yes	1581.54
E-HCAD-10	yes	1154.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA6, NR5A1

miRNA regulators (miRDB)

47 targeting CYB5A, 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-656-3P	100.00	72.15	2788
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-1244	99.33	68.38	832
HSA-MIR-5582-5P	99.27	71.42	1879

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 38)

• mitochondrial and microsomal cytochromes b(5) exhibit divergent structural and biophysical characteristics (PMID:14733950)
• Colocalization of CytB5 and P450c17 strongly supports the view that CytB5 plays an important role in the regulation of the androgen biosynthetic pathway in the fetal and adult human. (PMID:14985252)
• Data suggest that cytochrome b5 and phosphorylation enhance 17,20 lyase activity independently of each other, probably by increasing the interaction between P450c17 and NADPH-cytochrome P450 oxidoreductase. (PMID:15687493)
• cytochrome b5 gene transcription is regulated by Sp3, GATA-6, and steroidogenic factor 1 in human adrenal NCI-H295A cells (PMID:15831526)
• CYP2E1-b(5) complex model was constructed, leading to improved insights into the protein interaction. (PMID:16679316)
• cytochrome b(5) has a role in the generation of hydroxyl radicals (PMID:17320757)
• Cytochrome b5 can alter multiple steps in the catalytic cycle via complex interactions with CYP2C9 and P450 reductase. (PMID:17446262)
• These data indicate that a naturally occurring variant in cyt b5, T60A, leads to modestly altered affinity for hydroxylamine substrates and dramatically reduced cyt b5 expression. (PMID:17622936)
• The recombinant fused enzymes CYP3A4-truncated (t)-P450 reductase-t-b5 (3RB) and CYP3A4-t-b5-t-P450 reductase (3BR) in yeast microsomes showed a higher specific activity in 6beta-hydroxylation of testosterone than did the reconstitution premixes. (PMID:17691855)
• Cytochrome b(5) rather than O(2)(*-) plays a major role in the activation of IDO in human cells. (PMID:18299324)
• novel cSNPs associated with significantly altered protein expression and/or hydroxylamine reduction activities, but only minimally impact overall observed phenotypic variability (PMID:19997042)
• We demonstrated 17,20-lyase deficiency due to an aberrant CytB5. (PMID:20080843)
• Cygb has a nitric-oxide dioxygenase function and ascorbate and cytochrome b(5) have roles as reductants (PMID:20511233)
• Human adrenal cells that express both 3beta-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) contribute to adrenal androstenedione production (PMID:21185375)
• Identification of the first human CYB5A missense mutation as the cause of isolated 17,20 lyase deficiency in three individuals with 46,XY disorder of sex development. (PMID:22170710)
• CYP17A1/b5 interaction is stronger when the hydroxylase substrate pregnenolone is present in the CYP17A1 active site than when the lyase substrate 17alpha-hydroxypregnenolone is in the active site. (PMID:23620596)
• CYB5A, which has a role in stearyl-CoA-desaturase activity, and RNF10, with an unknown role in weight regulating pathways, associated with adiposity and nominally increased the risk for T2D in American Indians. (PMID:24151200)
• Results define CYB5A as a novel prognostic factor for PDAC that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation. (PMID:24301457)
• Cytochrome b5 seems to play the key role in the formation of lipid-radical cycles in membranes. (PMID:24319746)
• raises the possibility that inhibition of CYB5A-deregulated downstream pathways, such as those involving TRAF6, may favor autophagy-mediated cancer cell death in selected subgroups of patients (PMID:24448000)
• both area and ratio of 3betaHSD and CYB5A double positive cells, which could represent the hybrid cells of zona fasciculate and zona reticularis, are correlated with adrenal development and could influence age-related serum androstenedione levels. (PMID:24832628)
• Variants in CYB5A and CYB5R3 should be considered in the evaluation of breast cancer risk in African American women. (PMID:25225034)
• Two acidic residues, Glu-48 and Glu-49, of cytochrome b5 are essential for stimulating the 17,20-lyase activity of CYP17A1. (PMID:25315771)
• CYB5A is the first RA susceptibility gene involved in androgen synthesis. Our functional analysis of SNP rs1790834 indicates that it contributes to the sex bias observed in RA. (PMID:25890314)
• We conclude that cytochrome b5 can influence the electronic conductivity of cytochrome P450c17 via allosteric, protein-protein interactions. (PMID:26587646)
• This study constructed a model of the membrane-bound full-length human P450 1A2-cyt b5 complex. The model was assembled from several parts using a multiscale modeling approach covering all-atom and coarse-grained molecular dynamics (MD). (PMID:26918755)
• Thus, although Mn-b5 binds to CYP17A1, it is unable to enhance the lyase reaction, strongly suggesting that cyt b5 has a redox effector role in enhancement of the CYP17A1 mediated lyase reaction necessary for androgen synthesis. (PMID:27297105)
• A homodimer model can resolve the conundrum as to how cytochrome P450 oxidoreductase and cytochrome b5 compete for the same binding site on cytochrome P450c17. (Review) (PMID:28000554)
• Data suggest that cytochrome b5 (CYB5) and cytochrome b5 reductase 3 (CYB5R3) can reduce human cytoglobin (CYGB) and zebrafish cytoglobins at rates up to 250-fold higher than those reported for the known physiological substrates, hemoglobin and myoglobin; the three proteins (CYB5+CYB5R3+CYGB) appear to constitute a metabolon involved in generation of nitric oxide. (PMID:28671819)
• Data suggest CYP17A1, with electron donor NADPH-P450 reductase, is inherently distributive enzyme but that some processivity is present; some 17alpha-hydroxy pregnenolone formed does not dissociate from CYP17A1 before conversion to dehydroepiandrosterone; CYB5A does not enhance reaction by decreasing k(off) of ligands of CYP17A1. (CYP17A1 = cytochrome P450, family 17, subfamily A, polypeptide 1; CYB5A = cytochrome b5) (PMID:28684414)
• Isolated 17, 20 Lyase Deficiency Secondary to a Novel CYB5A Variant: Comparison of Steroid Metabolomic Findings with Published Cases Provides Diagnostic Guidelines and Greater Insight into Its Biological Role. (PMID:33626548)
• Lack of association between CYB5A gene rs1790834 polymorphism and the response to leflunomide in women with rheumatoid arthritis. (PMID:34160668)
• Functional variants in cytochrome b5 type A (CYB5A) are enriched in Southwest American Indian individuals and associate with obesity. (PMID:35043601)
• An alternative CYB5A transcript is expressed in aneuploid ALL and enriched in relapse. (PMID:35436854)
• Regulating Effect of Cytochrome b5 Overexpression on Human Breast Cancer Cells. (PMID:35889429)
• The association between CYB5A gene rs1790834 polymorphism and clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis. (PMID:37289314)
• The N-terminal intrinsically disordered region of Ncb5or docks with the cytochrome b5 core to form a helical motif that is of ancient origin. (PMID:38041394)
• Proteomics, modeling, and fluorescence assays delineate cytochrome b5 residues involved in binding and stimulation of cytochrome P450 17A1 17,20-lyase. (PMID:38280431)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyb5a	ENSDARG00000098589
mus_musculus	Cyb5a	ENSMUSG00000024646
rattus_norvegicus	Cyb5a	ENSRNOG00000015205
rattus_norvegicus	Cyb5a	ENSRNOG00000070068
drosophila_melanogaster	CG6870	FBGN0032652
caenorhabditis_elegans	cytb-5.2	WBGENE00020931

Paralogs (1): CYB5B (ENSG00000103018)

Protein

Protein identifiers

Cytochrome b5 — P00167 (reviewed: P00167)

Alternative names: Microsomal cytochrome b5 type A

All UniProt accessions (3): A0A384ME44, J3KNC7, P00167

UniProt curated annotations — full annotation on UniProt →

Function. Cytochrome b5 is a membrane-bound hemoprotein functioning as an electron carrier for several membrane-bound oxygenases.

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane Cytoplasm.

Disease relevance. Methemoglobinemia and ambiguous genitalia (METAG) [MIM:250790] An autosomal recessive disorder characterized by sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve, male undermasculinization, absent or disturbed pubertal development, decreased levels of erythrocyte cytochrome B5, and excessive amounts of methemoglobin in blood cells resulting in cyanosis and hypoxia. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the cytochrome b5 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P00167-1	1, Liver, Membrane-bound	yes
P00167-2	2, Erythrocyte, Cytoplasmic
P00167-3	3

RefSeq proteins (3): NP_001177736, NP_001905, NP_683725* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001199	Cyt_B5-like_heme/steroid-bd	Domain
IPR018506	Cyt_B5_heme-BS	Binding_site
IPR036400	Cyt_B5-like_heme/steroid_sf	Homologous_superfamily
IPR050668	Cytochrome_b5	Family

Pfam: PF00173

UniProt features (36 total): sequence conflict 8, helix 6, strand 5, splice variant 3, turn 3, modified residue 3, sequence variant 2, binding site 2, initiator methionine 1, chain 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2I96	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00167-F1	80.64	0.46

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): 44 (axial binding residue); 68 (axial binding residue)

Post-translational modifications (3): 2, 10, 19

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-196836	Vitamin C (ascorbate) metabolism
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane

MSigDB gene sets: 443 (showing top): CREL_01, MODULE_52, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GRUETZMANN_PANCREATIC_CANCER_DN, KYNG_DNA_DAMAGE_BY_4NQO, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GTGCCTT_MIR506, NFKB_C, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, HSIAO_LIVER_SPECIFIC_GENES, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (0):

GO Molecular Function (4): enzyme binding (GO:0019899), heme binding (GO:0020037), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrial outer membrane (GO:0005741), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
protein binding	1
tetrapyrrole binding	1
cation binding	1
binding	1
mitochondrial membrane	1
organelle outer membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2889 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYB5A	CYB5R3	P00387	999
CYB5A	POR	P16435	997
CYB5A	CYCS	P00001	995
CYB5A	CYB5RL	Q6IPT4	994
CYB5A	CYB5R1	Q9UHQ9	993
CYB5A	CYB5R2	Q6BCY4	992
CYB5A	MB	P02144	989
CYB5A	SCD	O00767	979
CYB5A	CYP17A1	P05093	978
CYB5A	CYB5R4	Q7L1T6	965
CYB5A	CYP3A4	P05184	944
CYB5A	CYP2E1	P05181	941
CYB5A	NENF	Q9UMX5	938
CYB5A	CYP2B6	P20813	893
CYB5A	CYP1A2	P05177	848

IntAct

81 interactions, top by confidence:

A	B	Type	Score
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
CYB5A		psi-mi:“MI:0915”(physical association)	0.560
GRN	CYB5A	psi-mi:“MI:0915”(physical association)	0.560
CYB5A	PMP22	psi-mi:“MI:0915”(physical association)	0.560
CYB5A	WFS1	psi-mi:“MI:0915”(physical association)	0.560
CYB5A	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
CYB5A	RNF11	psi-mi:“MI:0915”(physical association)	0.560
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
CYP3A5	CYB5A	psi-mi:“MI:0407”(direct interaction)	0.440
PROM1	CYB5A	psi-mi:“MI:0915”(physical association)	0.370
CYB5A	CYP2W1	psi-mi:“MI:0915”(physical association)	0.370
CYB5A	UGT1A4	psi-mi:“MI:0915”(physical association)	0.370
CYB5A		psi-mi:“MI:0915”(physical association)	0.370
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
rep	GPR89A	psi-mi:“MI:0914”(association)	0.350

BioGRID (176): CYB5A (Affinity Capture-MS), CYB5A (Affinity Capture-MS), CYB5A (Affinity Capture-MS), CYB5A (Affinity Capture-MS), ISYNA1 (Co-fractionation), ENDOD1 (Affinity Capture-MS), HSPA14 (Affinity Capture-MS), RABGAP1L (Affinity Capture-MS), AGPAT4 (Affinity Capture-MS), TAB1 (Affinity Capture-MS), BCAP31 (Affinity Capture-MS), SNX2 (Affinity Capture-MS), CYB5A (Affinity Capture-RNA), CYB5A (Affinity Capture-MS), COX6C (Co-fractionation)

ESM2 similar proteins: B7G7Y7, B7GCG7, O04354, O13995, O22704, O43169, O48845, O74875, O94391, P00167, P00169, P00170, P00171, P00172, P00173, P00174, P00175, P04166, P34454, P34476, P35848, P40312, P40934, P49096, P49097, P49098, P49099, P49100, P56395, Q10352, Q12091, Q29HF1, Q42342, Q54LA1, Q55CU8, Q5RDJ5, Q60YT6, Q7YZW5, Q874I5, Q9CQX2

Diamond homologs: A0A0C5PRW9, A4FV48, A4IFP3, A4UVI1, A8MWK0, B2KKL4, B7GCG7, B8MKR3, B8R1K0, C8VJR5, D8X2C5, O04354, O22704, O43169, O48845, O60427, O74875, O94391, O95864, P00167, P00168, P00169, P00170, P00171, P00172, P00173, P00174, P00175, P04166, P09437, P32953, P40312, P40934, P49096, P49097, P49098, P49099, P49100, P56395, P82291

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	5	25.8×	5e-04
Maturation of spike protein	5	20.4×	7e-04
Maturation of DENV proteins	5	16.3×	1e-03
ER-Phagosome pathway	5	10.0×	8e-03
SRP-dependent cotranslational protein targeting to membrane	6	9.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	10
Likely benign	4
Benign	5

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
230	NM_148923.4(CYB5A):c.130-2A>G	Pathogenic
524200	NM_148923.4(CYB5A):c.81G>A (p.Trp27Ter)	Likely pathogenic
524201	NM_148923.4(CYB5A):c.131A>T (p.His44Leu)	Likely pathogenic

SpliceAI

1024 predictions. Top by Δscore:

Variant	Effect	Δscore
18:74253661:ACCAA:A	acceptor_gain	1.0000
18:74253662:CCAA:C	acceptor_gain	1.0000
18:74253662:CCAAC:C	acceptor_gain	1.0000
18:74253663:CAA:C	acceptor_gain	1.0000
18:74253663:CAAC:C	acceptor_gain	1.0000
18:74253664:AA:A	acceptor_gain	1.0000
18:74253664:AACT:A	acceptor_loss	1.0000
18:74253665:ACTAG:A	acceptor_loss	1.0000
18:74253666:C:CC	acceptor_gain	1.0000
18:74253666:C:T	acceptor_loss	1.0000
18:74263343:ACTT:A	donor_loss	1.0000
18:74263344:CT:C	donor_loss	1.0000
18:74263344:CTTA:C	donor_gain	1.0000
18:74263345:TTA:T	donor_loss	1.0000
18:74263346:TAC:T	donor_loss	1.0000
18:74263347:A:AC	donor_gain	1.0000
18:74263347:AC:A	donor_loss	1.0000
18:74263348:C:CG	donor_gain	1.0000
18:74263348:CT:C	donor_gain	1.0000
18:74263348:CTG:C	donor_gain	1.0000
18:74263348:CTGG:C	donor_gain	1.0000
18:74263348:CTGGA:C	donor_gain	1.0000
18:74263473:GGATG:G	acceptor_gain	1.0000
18:74263474:GATG:G	acceptor_gain	1.0000
18:74263476:TG:T	acceptor_gain	1.0000
18:74263477:GCTGT:G	acceptor_loss	1.0000
18:74263478:C:CA	acceptor_loss	1.0000
18:74263478:C:CC	acceptor_gain	1.0000
18:74291743:TCACC:T	donor_loss	1.0000
18:74291745:A:AC	donor_gain	1.0000

AlphaMissense

892 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:74263403:G:C	H68Q	0.999
18:74263403:G:T	H68Q	0.999
18:74263404:T:C	H68R	0.999
18:74263405:G:C	H68D	0.999
18:74263418:A:C	F63L	0.999
18:74263418:A:T	F63L	0.999
18:74263420:A:G	F63L	0.999
18:74263475:A:C	H44Q	0.999
18:74263475:A:T	H44Q	0.999
18:74263476:T:C	H44R	0.999
18:74291756:A:C	F40L	0.999
18:74291756:A:T	F40L	0.999
18:74291758:A:G	F40L	0.999
18:74263362:C:T	G82E	0.998
18:74263401:G:A	S69F	0.998
18:74263405:G:T	H68N	0.998
18:74263419:A:G	F63S	0.998
18:74263455:A:G	L51S	0.998
18:74263477:G:C	H44D	0.998
18:74253621:A:T	V123D	0.997
18:74263362:C:A	G82V	0.997
18:74263392:G:T	A72D	0.997
18:74263419:A:C	F63C	0.997
18:74263467:C:A	G47V	0.997
18:74263467:C:T	G47E	0.997
18:74263470:C:T	G46D	0.997
18:74263473:G:T	P45H	0.997
18:74263474:G:A	P45S	0.997
18:74291757:A:C	F40C	0.997
18:74291757:A:G	F40S	0.997

dbSNP variants (sampled 300 via entrez): RS1000025365 (18:74265303 C>T), RS1000036873 (18:74264962 A>G), RS1000111714 (18:74260629 G>A), RS1000286712 (18:74252428 C>G,T), RS1000319859 (18:74266275 A>G), RS1000337305 (18:74252112 C>A), RS1000372453 (18:74293901 C>G,T), RS1000415103 (18:74254035 G>C), RS1000497529 (18:74271662 G>C), RS1000533424 (18:74260300 G>T), RS1000582693 (18:74265051 G>A), RS1000649176 (18:74266543 C>T), RS1000710461 (18:74270157 G>A), RS1000865251 (18:74276049 G>T), RS1000946666 (18:74260084 T>C)

Disease associations

OMIM: gene MIM:613218 | disease phenotypes: MIM:250790

GenCC curated gene-disease

Disease	Classification	Inheritance
methemoglobinemia type 4	Strong	Autosomal recessive
46,XY disorder of sex development due to isolated 17,20-lyase deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
methemoglobinemia type 4	Definitive	AR

Mondo (2): methemoglobinemia type 4 (MONDO:0009605), (MONDO:0019597)

Orphanet (1): Autosomal recessive methemoglobinemia (Orphanet:621)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000028	Cryptorchidism
HP:0000033	Ambiguous genitalia, male
HP:0000037	Male pseudohermaphroditism
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000144	Decreased fertility
HP:0000147	Polycystic ovaries
HP:0000252	Microcephaly
HP:0000565	Esotropia
HP:0000592	Blue sclerae
HP:0000707	Abnormality of the nervous system
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000815	Hypergonadotropic hypogonadism
HP:0000823	Delayed puberty
HP:0000868	Decreased fertility in females
HP:0000939	Osteoporosis
HP:0000961	Cyanosis
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001597	Abnormal nail morphology

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_2706	Blood protein levels	3.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567102	Methemoglobinemia Type IV (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6170 (SINGLE PROTEIN)

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

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs75160992	CYB5A		0.00	0
rs77005399	CYB5A		0.00	0
rs7663179	CYB5A		0.00	0
rs1790834	CYB5A		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	7
bisphenol A	increases expression, affects expression	3
trichostatin A	increases expression, affects cotreatment	3
Tetrachlorodibenzodioxin	increases expression	3
methylmercuric chloride	decreases expression	2
sodium arsenite	affects expression, decreases expression	2
1-phenylazo-2-naphthol	decreases reaction, increases oxidation, increases reaction	2
mercuric bromide	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Dexamethasone	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
bisphenol F	increases expression	1
testosterone enanthate	affects cotreatment, decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
2-anthramine	increases activity, increases reaction	1
benzo(b)fluoranthene	increases expression	1
glycidyl methacrylate	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
N-nitroso(di-n-propyl)amine	increases activity, increases reaction	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases activity, increases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
diisopropyl 1,3-dithiol-2-ylidenemalonate	increases metabolic processing, increases expression	1

ChEMBL screening assays

5 unique, capped per target: 4 admet, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3538988	ADMET	Drug metabolism assessed as cytochrome b5 (unknown origin)-mediated (5-hydroxy-1-pentyl-1H-indol-3-yl)(naphthalen-1-yl)methanone formation at 10 uM after 90 mins by LC-MS/MS analysis in presence of oxidoreductase	Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. — Drug Metab Dispos
CHEMBL979984	Binding	Inhibition of cytochrome b5 at >10 uM	Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1M5	Abcam K-562 CYB5A KO	Cancer cell line	Female
CVCL_D2IQ	Abcam Raji CYB5A KO	Cancer cell line	Male
CVCL_UQ37	Abcam Jurkat CYB5A KO	Cancer cell line	Male

Clinical trials (associated diseases)

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