MCM2

Chr 3AD

minichromosome maintenance complex component 2

Also known as: BM28, CCNL1, CDCL1, D3S3194, DFNA70, MITOTIN, cdc19

NCBI Gene: 4171 ENSG00000073111 UniProt: P33993 OMIM: 116945

The MCM2 protein is a core component of the MCM2-7 replicative helicase complex that is essential for DNA replication initiation and elongation in eukaryotic cells. Biallelic MCM2 mutations cause primary microcephaly and growth retardation, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants in the general population, reflecting its critical role in fundamental cellular processes.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Oct 2012]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.581 OMIM phenotype

Clinical Summary— MCM2

🧬

Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 217 VUS of 399 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.000

Z-score 3.61

OE 0.38 (0.25–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.68Z-score

OE missense 0.81 (0.75–0.87)

490 obs / 606.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.25–0.58)

0≤0.351.4

Missense OE?0.81 (0.75–0.87)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 15 / 39.5Missense obs/exp: 490 / 606.2Syn Z: -1.36

This gene — mechanism propensity

0.75top 25%

GOF

0.5072th %ile

LOF

0.3843th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

399 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS217

Likely Benign134

Benign26

Conflicting10

Likely Pathogenic

217

VUS

134

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	1	0	0	2
VUS	2	208	6	1	217
Likely Benign	0	16	43	75	134
Benign	0	4	10	12	26
Conflicting	—				10
Total	3	229	59	88	389

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap MCM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →