CYB5R3

Chr 22AR

cytochrome b5 reductase 3

Also known as: B5R, DIA1

NCBI Gene: 1727 ENSG00000100243 UniProt: P00387 OMIM: 613213

Cytochrome b5 reductase catalyzes the reduction of cytochrome b5 using NADH, with the membrane-bound form functioning in fatty acid metabolism and cholesterol biosynthesis, and the soluble erythrocyte form reducing methemoglobin. Mutations cause autosomal recessive methemoglobinemia, which can be limited to erythrocytes (type I) or involve multiple organ systems with neurological manifestations (type II). The gene shows low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.852 OMIM phenotypes

Clinical Summary— CYB5R3

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Gene-Disease Validity (ClinGen)

methemoglobinemia due to deficiency of methemoglobin reductase · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

39 unique Pathogenic / Likely Pathogenic· 134 VUS of 323 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?

0.85LOEUF

pLI 0.000

Z-score 2.03

OE 0.49 (0.29–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.42Z-score

OE missense 1.08 (0.97–1.21)

222 obs / 205.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.49 (0.29–0.85)

0≤0.351.4

Missense OE?1.08 (0.97–1.21)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 9 / 18.4Missense obs/exp: 222 / 205.1Syn Z: 0.12

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCYB5R3-related methemoglobinemia due to deficiency of methemoglobin reductaseLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7228th %ile

GOF

0.75top 25%

LOF

0.2189th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

323 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic15

VUS134

Likely Benign78

Benign46

Conflicting13

Pathogenic

Likely Pathogenic

134

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	10	3	0	24
Likely Pathogenic	3	11	1	0	15
VUS	3	125	6	0	134
Likely Benign	0	6	35	37	78
Benign	0	3	38	5	46
Conflicting	—				13
Total	17	155	83	42	310

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap CYB5R3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →