C8ORF76

Chr 8

chromosome 8 open reading frame 76

NCBI Gene: 84933 ENSG00000189376 UniProt: Q96K31

This gene encodes a protein involved in mitochondrial ribosome assembly and function. Mutations cause autosomal recessive mitochondrial complex I deficiency, presenting with severe early-onset encephalomyopathy, developmental delay, and metabolic acidosis. The gene shows minimal constraint against loss-of-function variants (very low pLI), consistent with its recessive inheritance pattern.

Research

ResearchGenerating clinical summary…

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.61

LOEUF

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Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.61LOEUF

pLI 0.000

Z-score -0.45

OE 1.11 (0.78–1.61)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.00Z-score

OE missense 1.00 (0.89–1.13)

187 obs / 187.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.11 (0.78–1.61)

0≤0.351.4

Missense OE?1.00 (0.89–1.13)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 20 / 18.0Missense obs/exp: 187 / 187.1Syn Z: 0.12

Background carrier burden — how many people carry a rare variant somewhere in C8ORF76?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

482 rare PASS variants

Rare truncating (LoF)

1 in 2,100

94 rare PASS variants

Rare synonymous (reference)

1 in 410

178 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for C8ORF76. 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 190	1 in 2,500
South Asian	~43k	1 in 83	1 in 980
Remaining (unassigned)	~30k	1 in 84	1 in 2,300
European (Finnish)	~27k	1 in 640	1 in 4,600
Admixed American	~22k	1 in 160	1 in 1,000
African / African American	~21k	1 in 280	1 in 940
East Asian	~20k	1 in 160	1 in 4,000
Ashkenazi Jewish	~13k	1 in 300	1 in 1,200
Middle Eastern	~2,884	1 in 120	≈ 1 in 1,400

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 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓