CDC45

Chr 22AR

cell division cycle 45

Also known as: CDC45L, CDC45L2, MGORS7, PORC-PI-1

NCBI Gene: 8318 ENSG00000093009 UniProt: O75419 OMIM: 603465

The CDC45 protein is a core component of the CMG helicase complex that unwinds template DNA during chromosomal DNA replication initiation. Mutations cause Meier-Gorlin syndrome 7, an autosomal recessive disorder characterized by primordial dwarfism, microcephaly, and ear anomalies. The gene is highly constrained against loss-of-function variation (pLI near 1, LOEUF 0.598), reflecting its essential role in DNA replication.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene was identified by its strong similarity with Saccharomyces cerevisiae Cdc45, an essential protein required to the initiation of DNA replication. Cdc45 is a member of the highly conserved multiprotein complex including Cdc6/Cdc18, the minichromosome maintenance proteins (MCMs) and DNA polymerase, which is important for early steps of DNA replication in eukaryotes. This protein has been shown to interact with MCM7 and DNA polymerase alpha. Studies of the similar gene in Xenopus suggested that this protein play a pivotal role in the loading of DNA polymerase alpha onto chromatin. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.601 OMIM phenotype

Clinical Summary— CDC45

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Gene-Disease Validity (ClinGen)

Meier-Gorlin syndrome 7 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

24 unique Pathogenic / Likely Pathogenic· 145 VUS of 392 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.000

Z-score 3.46

OE 0.38 (0.25–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.83Z-score

OE missense 0.88 (0.80–0.96)

315 obs / 359.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.25–0.60)

0≤0.351.4

Missense OE?0.88 (0.80–0.96)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 14 / 36.6Missense obs/exp: 315 / 359.2Syn Z: 0.73

ClinVar Variant Classifications

392 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic12

VUS145

Likely Benign155

Benign37

Conflicting12

Pathogenic

Likely Pathogenic

145

VUS

155

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	0	1	0	12
Likely Pathogenic	5	5	1	1	12
VUS	2	132	8	3	145
Likely Benign	0	8	85	62	155
Benign	0	0	31	6	37
Conflicting	—				12
Total	18	145	126	72	373

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

392 pathogenic / likely-pathogenic (of 411) ClinVar copy-number / structural variants overlap CDC45 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →