C15ORF40

Chr 15

chromosome 15 open reading frame 40

NCBI Gene: 123207 ENSG00000169609 UniProt: Q8WUR7

The protein encoded by this gene localizes to the mitochondrion, though its specific function remains unclear. Mutations cause autosomal recessive intellectual disability with seizures and growth retardation, typically manifesting in early childhood. The gene shows relatively low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq

Located in mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.96

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.96LOEUF

pLI 0.186

Z-score 1.66

OE 0.30 (0.12–0.96)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.63Z-score

OE missense 1.19 (1.01–1.39)

106 obs / 89.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.30 (0.12–0.96)

0≤0.351.4

Missense OE?1.19 (1.01–1.39)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 2 / 6.6Missense obs/exp: 106 / 89.4Syn Z: -1.39

Background carrier burden — how many people carry a rare variant somewhere in C15ORF40?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

398 rare PASS variants

Rare truncating (LoF)

1 in 630

81 rare PASS variants

Rare synonymous (reference)

1 in 290

159 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for C15ORF40. 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 160	1 in 990
South Asian	~43k	1 in 110	1 in 620
Remaining (unassigned)	~30k	1 in 98	1 in 430
European (Finnish)	~27k	1 in 390	none seen
Admixed American	~22k	1 in 110	1 in 820
African / African American	~21k	1 in 170	1 in 2,200
East Asian	~20k	1 in 150	1 in 720
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 5,100
Middle Eastern	~2,884	1 in 140	≈ 1 in 1,000

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