CYB5R3

Chr 22AR

cytochrome b5 reductase 3

Also known as: B5R, DIA1

NCBI Gene: 1727ENSG00000100243UniProt: P00387

This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

Methemoglobinemia, type IMIM #250800
AR
Methemoglobinemia, type IIMIM #250800
AR
UniProtMethemoglobinemia CYB5R3-related
358
ClinVar variants
55
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CYB5R3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
55 Pathogenic / Likely Pathogenic· 117 VUS of 358 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.85LOEUF
pLI 0.000
Z-score 2.03
OE 0.49 (0.29–0.85)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.42Z-score
OE missense 1.08 (0.97–1.21)
222 obs / 205.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.49 (0.29–0.85)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (0.97–1.21)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 9 / 18.4Missense obs/exp: 222 / 205.1Syn Z: 0.12

ClinVar Variant Classifications

358 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic12
VUS117
Likely Benign56
Benign8
Conflicting9
43
Pathogenic
12
Likely Pathogenic
117
VUS
56
Likely Benign
8
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
6
35
0
43
Likely Pathogenic
1
9
2
0
12
VUS
2
109
6
0
117
Likely Benign
0
6
25
25
56
Benign
0
1
3
4
8
Conflicting
—9
Total51317129245

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

View in ClinVar →

Protein Context — Lollipop Plot

CYB5R3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CYB5R3-related methemoglobinemia due to deficiency of methemoglobin reductase

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Methemoglobinemia, type I

MIM #250800

Molecular basis of disorder known

Autosomal recessive

Methemoglobinemia, type II

MIM #250800

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Recommendations for diagnosis and treatment of methemoglobinemia.
Iolascon A et al.·Am J Hematol
2021Review
VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.
Wang Z et al.·Autophagy
2024
Identification of metabolism-related subtypes and feature genes in Alzheimer's disease.
Lian P et al.·J Transl Med
2023
The secreted metabolite sensor CtBP2 links metabolism to healthy lifespan.
Sekiya M et al.·Nat Aging
2025
Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women.
Blanke KL et al.·Cancer Causes Control
2014
Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia.
Ullah A et al.·Medicina (Kaunas)
2023Cohort
Global proteomics and affinity mass spectrometry analysis of human Schwann cells indicates that variation in and loss of neurofibromin (NF1) alters protein expression and cellular and mitochondrial metabolism.
Fay CX et al.·Sci Rep
2025
Benign prostatic hyperplasia/obstruction ameliorated using a soluble guanylate cyclase activator.
Zabbarova IV et al.·J Pathol
2022
CYB5R3 homozygous pathogenic variant as a rare cause of cyanosis in the newborn.
Molina Herranz D et al.·Clin Biochem
2022Case report
Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia.
Gupta V et al.·Hum Mutat
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Untargeted Serum Proteomics in the Fontan Circulation Reveals Three Distinct Molecular Signatures of Fontan Physiology with CYB5R3 Among Key Proteins.
Blaha A et al.·Int J Mol Sci
2026🔓 Open Access
Adaptations of mitochondrial, autophagy and nutrient sensing pathways in the liver from long-lived mice overexpressing CYB5R3 are sex-dependent and involve inter-organ responses.
Sánchez-Mendoza LM et al.·Geroscience
2025
Rare Case of Homozygosity for CYB5R3 Variant c.235C > T p.(Arg79Trp) Causing Type II Methemoglobinemia.
Bendtsen SK et al.·Hemoglobin
2025
Exploration of the multiomics-based mechanisms of Gancao Nourishing-Yin decoction in regulating mitochondrial metabolic genes CYB5R3 and PICK1 to influence glioma progression.
Chen Y et al.·Discov Oncol
2025🔓 Open AccessFunctional
A novel stoploss mutation CYB5R3 c.906A>G(p.*302Trpext*42) involved in the pathogenesis of hereditary methemoglobinemia.
He KY et al.·Clin Chim Acta
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools