ORC2

Chr 2

origin recognition complex subunit 2

Also known as: ORC2L

NCBI Gene: 4999 ENSG00000115942 UniProt: Q13416 OMIM: 601182

The ORC2 protein is a subunit of the origin recognition complex that is essential for initiating DNA replication in eukaryotic cells by binding to replication origins and recruiting additional replication factors. Mutations in ORC2 cause Meier-Gorlin syndrome, an autosomal recessive disorder characterized by primordial dwarfism, microtia, and absent or underdeveloped patellae. The gene is highly constrained against loss-of-function variants, reflecting its essential role in cellular replication.

OMIM ResearchSummary from RefSeq, UniProt

The origin recognition complex (ORC) is a highly conserved six subunits protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is a subunit of the ORC complex. This protein forms a core complex with ORC3, -4, and -5. It also interacts with CDC45 and MCM10, which are proteins known to be important for the initiation of DNA replication. This protein has been demonstrated to specifically associate with the origin of replication of Epstein-Barr virus in human cells, and is thought to be required for DNA replication from viral origin of replication. Alternatively spliced transcript variants have been found, one of which is a nonsense-mediated mRNA decay candidate. [provided by RefSeq, Oct 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.36

Clinical Summary— ORC2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.84) — some intolerance to loss-of-function variants.

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ClinVar Variants

59 VUS of 90 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.36LOEUF

pLI 0.844

Z-score 4.31

OE 0.18 (0.10–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.06Z-score

OE missense 0.82 (0.74–0.92)

235 obs / 285.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.10–0.36)

0≤0.351.4

Missense OE?0.82 (0.74–0.92)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 6 / 32.5Missense obs/exp: 235 / 285.4Syn Z: 1.47

This gene — mechanism propensity

0.3594th %ile

GOF

0.2099th %ile

LOF

0.64top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.36

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

90 submitted variants in ClinVar

ClinVar

Classification Summary

VUS59

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	59	59
Likely Benign	3	3
Benign	0	0
Total	62	62

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap ORC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →