CAB39

Chr 2

calcium binding protein 39

Also known as: CGI-66, MO25

NCBI Gene: 51719 ENSG00000135932 UniProt: Q9Y376 OMIM: 612174

The protein is a component of a complex that binds and activates the STK11/LKB1 kinase, stabilizing interactions within this serine/threonine protein kinase complex involved in intracellular signaling and protein phosphorylation regulation. Mutations cause autosomal recessive intellectual disability with seizures and language delay, typically presenting in early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.63), suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Enables protein serine/threonine kinase activator activity and protein serine/threonine kinase binding activity. Involved in cellular hypotonic response; intracellular signal transduction; and negative regulation of potassium ion transmembrane transport. Located in cytoplasm. Part of serine/threonine protein kinase complex. Implicated in hepatocellular carcinoma. Biomarker of hepatocellular carcinoma and pancreatic cancer. [provided by Alliance of Genome Resources, Jun 2026]

OMIM 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

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.63

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.63LOEUF

pLI 0.068

Z-score 2.64

OE 0.30 (0.16–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.38Z-score

OE missense 0.49 (0.41–0.59)

86 obs / 174.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.30 (0.16–0.63)

0≤0.351.4

Missense OE?0.49 (0.41–0.59)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 5 / 16.6Missense obs/exp: 86 / 174.6Syn Z: 1.17

Background carrier burden — how many people carry a rare variant somewhere in CAB39?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 370

282 rare PASS variants

Rare truncating (LoF)

1 in 16,000

18 rare PASS variants

Rare synonymous (reference)

1 in 270

165 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CAB39. 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 830	1 in 13,000
South Asian	~43k	1 in 360	≈ 1 in 8,800
Remaining (unassigned)	~30k	1 in 330	≈ 1 in 27,000
European (Finnish)	~27k	1 in 910	none seen
Admixed American	~22k	1 in 410	≈ 1 in 22,000
African / African American	~21k	1 in 610	none seen
East Asian	~20k	1 in 470	none seen
Ashkenazi Jewish	~13k	1 in 1,300	none seen
Middle Eastern	~2,884	1 in 400	none seen

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): 5 of 8 coding exons well covered in gnomAD exomes; exon 6 poorly covered; exons 4, 7 marginal. Genomes: 7 of 8 (exon 7 below).? see exons ↓