CYB561A3

Chr 11

cytochrome b561 family member A3

Also known as: CYBASC3, LCYTB

NCBI Gene: 220002 ENSG00000162144 UniProt: Q8NBI2 OMIM: 618757

The protein is a transmembrane reductase that reduces iron cations from Fe(3+) to Fe(2+) in late endosomes and lysosomes using ascorbate as an electron donor, facilitating cellular iron homeostasis. Mutations cause neurodevelopmental disorder with seizures, spasticity, and brain imaging abnormalities through autosomal recessive inheritance. The gene shows low constraint to loss-of-function variants, consistent with recessive disease.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable transmembrane ascorbate ferrireductase activity. Predicted to be involved in intracellular iron ion homeostasis. Located in lysosomal membrane. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.90

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.011

Z-score 1.81

OE 0.43 (0.22–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.90Z-score

OE missense 0.80 (0.69–0.93)

122 obs / 153.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.22–0.90)

0≤0.351.4

Missense OE?0.80 (0.69–0.93)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 5 / 11.7Missense obs/exp: 122 / 153.3Syn Z: 0.02

Background carrier burden — how many people carry a rare variant somewhere in CYB561A3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

321 rare PASS variants

Rare truncating (LoF)

1 in 2,500

70 rare PASS variants

Rare synonymous (reference)

1 in 370

120 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CYB561A3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 250	1 in 3,400
South Asian	~43k	1 in 130	1 in 1,700
Remaining (unassigned)	~30k	1 in 99	1 in 1,000
European (Finnish)	~27k	1 in 820	≈ 1 in 13,000
Admixed American	~22k	1 in 130	1 in 1,500
African / African American	~21k	1 in 110	1 in 1,600
East Asian	~20k	1 in 160	1 in 1,400
Ashkenazi Jewish	~13k	1 in 870	none seen
Middle Eastern	~2,884	1 in 190	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓