MN1

Chr 22AD

MN1 proto-oncogene, transcriptional regulator

Also known as: CEBALID, MGCR, MGCR1, MGCR1-PEN, dJ353E16.2

NCBI Gene: 4330 ENSG00000169184 UniProt: Q10571 OMIM: 156100

The MN1 protein is a transcriptional activator that regulates palate development by controlling TBX22 expression and promotes normal skull bone formation through osteoblast maturation. Mutations cause CEBALID syndrome, characterized by craniofacial abnormalities including cleft palate and skull defects, with autosomal dominant inheritance. This gene is extremely intolerant to loss-of-function variants (pLI >0.99), indicating that haploinsufficiency is likely not tolerated in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Meningioma 1 (MN1) contains two sets of CAG repeats. It is disrupted by a balanced translocation (4;22) in a meningioma, and its inactivation may contribute to meningioma 32 pathogenesis. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.092 OMIM phenotypes

Clinical Summary— MN1

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Gene-Disease Validity (ClinGen)

CEBALID syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

32 unique Pathogenic / Likely Pathogenic· 355 VUS of 490 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MN1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 5.41

OE 0.00 (0.00–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.16Z-score

OE missense 0.78 (0.73–0.83)

592 obs / 759.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.78 (0.73–0.83)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 0 / 34.0Missense obs/exp: 592 / 759.4Syn Z: 1.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMN1-related C-terminal truncation syndromeGOFAD

moderateMN1-related neurodevelopmental disorder with or without cleft palateLOFAD

This gene — mechanism propensity

0.2299th %ile

GOF

0.2099th %ile

LOF

0.88top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 91% of P/LP variants are LoF · LOEUF 0.09

GOF1 literature citation

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.

Literature Evidence

GOFMN1 C-terminal truncation (MCTT) syndrome is a newly recognized neurodevelopmental disorder due to heterozygous gain-of-function C-terminal truncating mutations clustering in the last or penultimate exon of MN1 gene (MIM: 156100).1

LOFThe mutations or deletions in this second group of patients were predicted to cause MN1 haploinsufficiency, and the phenotype was somewhat different than that observed in the first group of patients.2

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

References

ClinVar Variant Classifications

490 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic19

VUS355

Likely Benign75

Benign14

Conflicting9

Pathogenic

Likely Pathogenic

355

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	0	0	0	13
Likely Pathogenic	16	1	2	0	19
VUS	10	338	6	1	355
Likely Benign	0	31	3	41	75
Benign	0	3	6	5	14
Conflicting	—				9
Total	39	373	17	47	485

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap MN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →