CCS

Chr 11

copper chaperone for superoxide dismutase

NCBI Gene: 9973 ENSG00000173992 UniProt: O14618 OMIM: 603864

The copper chaperone for superoxide dismutase delivers copper to copper/zinc superoxide dismutase (SOD1), which is essential for cellular antioxidant defense. Mutations cause autosomal recessive amyotrophic lateral sclerosis, a progressive neurodegenerative disorder affecting motor neurons. The gene is not highly constrained against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected families.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Copper chaperone for superoxide dismutase specifically delivers Cu to copper/zinc superoxide dismutase and may activate copper/zinc superoxide dismutase through direct insertion of the Cu cofactor. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Refuted · disorder of copper metabolism · UD · ClinGen 2024

evidence has disproved this relationship

Active trials

2109

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.37

LOEUF

—

Mechanism

📖

GeneReview available — CCS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.37LOEUF

pLI 0.000

Z-score 0.53

OE 0.85 (0.54–1.37)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.40Z-score

OE missense 0.91 (0.80–1.04)

156 obs / 170.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.85 (0.54–1.37)

0≤0.351.4

Missense OE?0.91 (0.80–1.04)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 12 / 14.1Missense obs/exp: 156 / 170.7Syn Z: 1.16

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

366 rare PASS variants

Rare truncating (LoF)

1 in 900

78 rare PASS variants

Rare synonymous (reference)

1 in 590

140 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CCS. 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 890
South Asian	~43k	1 in 140	1 in 950
Remaining (unassigned)	~30k	1 in 140	1 in 750
European (Finnish)	~27k	1 in 170	1 in 990
Admixed American	~22k	1 in 120	1 in 900
African / African American	~21k	1 in 140	1 in 1,800
East Asian	~20k	1 in 72	1 in 1,800
Ashkenazi Jewish	~13k	1 in 280	1 in 2,200
Middle Eastern	~2,884	1 in 160	≈ 1 in 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): 7 of 8 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 8.? see exons ↓