CYB5A

Chr 18AR

cytochrome b5 type A

Also known as: CYB5, MCB5, METAG

NCBI Gene: 1528ENSG00000166347UniProt: P00167

The protein is a membrane-bound hemoprotein that functions as an electron carrier for several oxygenases and reduces methemoglobin to normal hemoglobin. Mutations cause autosomal recessive hereditary methemoglobinemia type IV, which can present with cyanosis and ambiguous genitalia. The gene shows low constraint to loss-of-function variation in the population.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

Methemoglobinemia and ambiguous genitaliaMIM #250790
AR
0
Active trials
10
Pubs (1 yr)
158
P/LP submissions
1%
P/LP missense
1.43
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— CYB5A
🧬
Gene-Disease Validity (ClinGen)
methemoglobinemia type 4 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
154 unique Pathogenic / Likely Pathogenic· 24 VUS of 200 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.43LOEUF
pLI 0.002
Z-score 0.78
OE 0.69 (0.36–1.43)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.09Z-score
OE missense 1.03 (0.85–1.24)
76 obs / 73.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.69 (0.36–1.43)
0≤0.351.4
Missense OE1.03 (0.85–1.24)
0≤0.61.4
Synonymous OE1.40
0≤1.21.6
LoF obs/exp: 5 / 7.3Missense obs/exp: 76 / 73.9Syn Z: -1.60
DN
0.6841th %ile
GOF
0.6541th %ile
LOF
0.2582th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic146
Likely Pathogenic8
VUS24
Likely Benign4
Benign5
Conflicting1
146
Pathogenic
8
Likely Pathogenic
24
VUS
4
Likely Benign
5
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
145
0
146
Likely Pathogenic
0
1
7
0
8
VUS
0
8
16
0
24
Likely Benign
0
1
1
2
4
Benign
0
0
3
2
5
Conflicting
—1
Total1101724188

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CYB5A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
The association between CYB5A gene rs1790834 polymorphism and clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.
Machaj F et al.·Clin Rheumatol
2023
An alternative CYB5A transcript is expressed in aneuploid ALL and enriched in relapse.
Bartsch L et al.·BMC Genom Data
2022
Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic.
Auchus RJ·J Steroid Biochem Mol Biol
2017Review
Functional variants in cytochrome b5 type A (CYB5A) are enriched in Southwest American Indian individuals and associate with obesity.
Day SE et al.·Obesity (Silver Spring)
2022Functional
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.
Shaunak M et al.·Horm Res Paediatr
2020Case report
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Micro RNA miR-726-3p targets CYB5A in Hen ovaries to modulate granulosa cell proliferation and differentiation.
Zhao J et al.·Sci Rep
2025Open Access
Haplotype-based association of CYB5A gene polymorphisms (rs1790834 and rs1790858) with polycystic ovary syndrome in a south Indian cohort.
Martin M et al.·Gene
2025Cohort
CYB5A promotes osteogenic differentiation of MC3T3-E1 cells through autophagy mediated by the AKT/mTOR/ULK1 signaling pathway.
Zhang Y et al.·Sci Rep
2025Open Access
Two families, two pathways: a case series of 46, XY DSD with 17α-hydroxylase deficiency and isolated 17,20-lyase deficiency due to novel CYB5A variant.
Garg R et al.·J Pediatr Endocrinol Metab
2025Cohort
Defects in CYB5A and CYB5B impact sterol-C4 oxidation in cholesterol biosynthesis and demonstrate regulatory roles of dimethyl sterols.
Ma MY et al.·Cell Rep
2024
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients