CAD

Chr 2AR

carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase

Also known as: CDG1Z, DEE50, EIEE50, GATD4

NCBI Gene: 790 ENSG00000084774 UniProt: O76075 OMIM: 114010

The CAD protein functions as a trifunctional enzyme catalyzing the first three steps of pyrimidine nucleotide biosynthesis (carbamoylphosphate synthetase II, aspartate transcarbamoylase, and dihydroorotase activities). Mutations cause developmental and epileptic encephalopathy 50 with autosomal recessive inheritance. This gene is highly constrained against loss-of-function variants, indicating its critical importance for normal cellular function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. This gene encodes a trifunctional protein which is associated with the enzymatic activities of the first 3 enzymes in the 6-step pathway of pyrimidine biosynthesis: carbamoylphosphate synthetase (CPS II), aspartate transcarbamoylase, and dihydroorotase. This protein is regulated by the mitogen-activated protein kinase (MAPK) cascade, which indicates a direct link between activation of the MAPK cascade and de novo biosynthesis of pyrimidine nucleotides. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 50MIM #616457

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · developmental and epileptic encephalopathy, 50 · AR · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

8194

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.25

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — CAD

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.25LOEUF

pLI 1.000

Z-score 8.09

OE 0.17 (0.12–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.34Z-score

OE missense 0.67 (0.63–0.71)

913 obs / 1363.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.17 (0.12–0.25)

0≤0.351.4

Missense OE?0.67 (0.63–0.71)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 19 / 110.9Missense obs/exp: 913 / 1363.6Syn Z: -0.93

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 31

2,399 rare PASS variants

Rare truncating (LoF)

1 in 1,100

215 rare PASS variants

Rare synonymous (reference)

1 in 28

1,295 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CAD. 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 37	1 in 1,100
South Asian	~43k	1 in 32	1 in 1,200
Remaining (unassigned)	~30k	1 in 26	1 in 1,600
European (Finnish)	~27k	1 in 110	1 in 2,600
Admixed American	~22k	1 in 28	1 in 1,500
African / African American	~21k	1 in 30	1 in 990
East Asian	~20k	1 in 33	1 in 1,500
Ashkenazi Jewish	~13k	1 in 76	1 in 1,600
Middle Eastern	~2,884	1 in 36	1 in 540

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 42 of 44 coding exons well covered in gnomAD exomes; exons 3, 16 marginal. Genomes: all 44.? see exons ↓