MAST1

Chr 19AD

microtubule associated serine/threonine kinase 1

Also known as: MCCCHCM, SAST

NCBI Gene: 22983 ENSG00000105613 UniProt: Q9Y2H9 OMIM: 612256

MAST1 encodes a microtubule-associated serine/threonine kinase that promotes microtubule stabilization and is required for proper cytoplasmic microtubule organization and chromosome alignment during cell division. Mutations cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations, following autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI >0.99), indicating that most loss-of-function mutations are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the microtubule-associated serine/threonine kinase (MAST) family. The protein encoded by this gene has an N-terminal serine/threonine kinase domain followed by a postsynaptic density protein-95/discs large/zona occludens-1 (PDZ) domain. In mouse and rat, the orthologous protein associates with the cytoskeleton and can bind both beta-2-syntrophin and neuronal nitric oxide synthase (nNOS) through its PDZ domain. In mouse and rat, this protein also co-localizes with dystrophin- and utrophin-associated protein complexes (DAPC/UAPC) in the vascular endothelium of the central nervous system. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— MAST1

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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

15 unique Pathogenic / Likely Pathogenic· 385 VUS of 720 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 6.98

OE 0.08 (0.04–0.16)

Highly constrained

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

Missense Constraint?

5.77Z-score

OE missense 0.50 (0.46–0.53)

514 obs / 1036.9 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.16)

0≤0.351.4

Missense OE?0.50 (0.46–0.53)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 5 / 66.3Missense obs/exp: 514 / 1036.9Syn Z: 3.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMAST1-related developmental disorderOTHERAD

This gene — mechanism propensity

0.4289th %ile

GOF

0.5071th %ile

LOF

0.78top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). 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 · LOEUF 0.16

DN1 literature citation

Literature Evidence

DNThe deletion of leu278 was associated with decreased levels of other MAST protein family members, whereas complete loss of Mast1 was associated with increased levels of other MAST proteins. These findings suggested that the leu278 allele acts in a dominant-negative manner.1

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

References

1.PMID 30449657 ↗

ClinVar Variant Classifications

720 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic10

VUS385

Likely Benign257

Benign41

Conflicting14

Pathogenic

Likely Pathogenic

385

VUS

257

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	4	0	0	5
Likely Pathogenic	0	10	0	0	10
VUS	20	344	19	2	385
Likely Benign	1	32	86	138	257
Benign	0	8	14	19	41
Conflicting	—				14
Total	22	398	119	159	712

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap MAST1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →