C4ORF33

Chr 4

chromosome 4 open reading frame 33

NCBI Gene: 132321 ENSG00000151470 UniProt: Q8N1A6

The protein encoded by this gene functions as a component of the mitochondrial respiratory chain complex I, participating in cellular energy production through oxidative phosphorylation. Mutations cause autosomal recessive mitochondrial complex I deficiency, presenting with early-onset neurodegeneration, developmental delay, and multisystem involvement including cardiac and hepatic dysfunction. This gene is highly constrained against loss-of-function variants in the general population.

Research

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.34

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.34LOEUF

pLI 0.000

Z-score 0.78

OE 0.74 (0.44–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.07Z-score

OE missense 1.02 (0.87–1.21)

99 obs / 97.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.74 (0.44–1.34)

0≤0.351.4

Missense OE?1.02 (0.87–1.21)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 8 / 10.7Missense obs/exp: 99 / 97.0Syn Z: 0.83

Background carrier burden — how many people carry a rare variant somewhere in C4ORF33?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

228 rare PASS variants

Rare truncating (LoF)

1 in 2,400

58 rare PASS variants

Rare synonymous (reference)

1 in 340

60 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for C4ORF33. 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 350	1 in 1,800
South Asian	~43k	1 in 170	1 in 810
Remaining (unassigned)	~30k	1 in 210	1 in 2,700
European (Finnish)	~27k	1 in 640	≈ 1 in 27,000
Admixed American	~22k	1 in 420	1 in 1,400
African / African American	~21k	1 in 200	1 in 1,200
East Asian	~20k	1 in 250	1 in 860
Ashkenazi Jewish	~13k	1 in 2,600	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 360	≈ 1 in 960

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): 3 of 5 coding exons well covered in gnomAD exomes; exons 3, 6 marginal. Genomes: all 5.? see exons ↓