CTPS2

Chr X

CTP synthase 2

Also known as: GATD5B

NCBI Gene: 56474 ENSG00000047230 UniProt: Q9NRF8 OMIM: 300380

CTP synthase 2 catalyzes the rate-limiting step in cytosine nucleotide synthesis, converting UTP to CTP for DNA, RNA, and phospholipid production. Biallelic mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and cortical visual impairment. The gene is highly constrained against loss-of-function variants, reflecting its essential role in nucleotide metabolism.

OMIM ResearchSummary from UniProt

The protein encoded by this gene catalyzes the formation of CTP from UTP with the concomitant deamination of glutamine to glutamate. This protein is the rate-limiting enzyme in the synthesis of cytosine nucleotides, which play an important role in various metabolic processes and provide the precursors necessary for the synthesis of RNA and DNA. Cancer cells that exhibit increased cell proliferation also exhibit an increased activity of this encoded protein. Thus, this protein is an attractive target for selective chemotherapy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.819

Z-score 3.70

OE 0.17 (0.08–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.59Z-score

OE missense 0.51 (0.44–0.60)

116 obs / 225.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.08–0.39)

0≤0.351.4

Missense OE?0.51 (0.44–0.60)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 4 / 23.2Missense obs/exp: 116 / 225.4Syn Z: 0.60

Background carrier burden — how many people carry a rare variant somewhere in CTPS2?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

335 rare PASS variants

Rare truncating (LoF)

1 in 7,300

36 rare PASS variants

Rare synonymous (reference)

1 in 260

172 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CTPS2. 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)	~561k	1 in 210	1 in 7,700
South Asian	~36k	1 in 170	≈ 1 in 18,000
Remaining (unassigned)	~31k	1 in 220	none seen
European (Finnish)	~27k	1 in 1,300	≈ 1 in 6,700
Admixed American	~23k	1 in 240	≈ 1 in 10,000
African / African American	~21k	1 in 150	≈ 1 in 10,000
East Asian	~20k	1 in 330	1 in 2,100
Ashkenazi Jewish	~13k	1 in 970	≈ 1 in 4,300
Middle Eastern	~2,758	1 in 230	≈ 1 in 1,500

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