MAST1

Chr 19AD

microtubule associated serine/threonine kinase 1

ENSG00000105613UniProt: Q7Z460

Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules. Involved in the nucleation of noncentrosomal microtubules originating from the trans-Golgi network (TGN). Required for the polarization of the cytoplasmic microtubule arrays in migrating cells towards the leading edge of the cell. May act at the cell cortex to enhance the frequency of rescue of depolymerizing microtubules by attaching their plus-ends to cortical platforms composed of ERC1 and PHLDB2. This cortical microtubule stabilizing activity is regulated at least in part by phosphatidylinositol 3-kinase signaling. Also performs a similar stabilizing function at the kinetochore which is essential for the bipolar alignment of chromosomes on the mitotic spindle

Primary Disease Associations & Inheritance

Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformationsMIM #618273
AD
445
ClinVar variants
27
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MAST1
⚡
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.
📋
ClinVar Variants
27 Pathogenic / Likely Pathogenic· 247 VUS of 445 total submissions
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.04–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.46–0.53)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.82
0≤1.21.6
LoF obs/exp: 5 / 66.3Missense obs/exp: 514 / 1036.9Syn Z: 3.03

ClinVar Variant Classifications

445 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic9
VUS247
Likely Benign141
Benign22
Conflicting8
18
Pathogenic
9
Likely Pathogenic
247
VUS
141
Likely Benign
22
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
17
0
18
Likely Pathogenic
0
5
4
0
9
VUS
11
213
22
1
247
Likely Benign
1
16
43
81
141
Benign
0
6
7
9
22
Conflicting
—8
Total122419391445

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

View in ClinVar →

Protein Context — Lollipop Plot

MAST1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MAST1-related developmental disorder

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations

MIM #618273

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CRISPR/Cas9-based genome-wide screening for deubiquitinase subfamily identifies USP1 regulating MAST1-driven cisplatin-resistance in cancer cells.
Tyagi A et al.·Theranostics
2022
USP28 promotes tumorigenesis and cisplatin resistance by deubiquitinating MAST1 protein in cancer cells.
Karapurkar JK et al.·Cell Mol Life Sci
2024
Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations.
Tripathy R et al.·Neuron
2018
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.
Girard E et al.·Int J Cancer
2019
Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy.
Martínez-Rubio D et al.·Int J Mol Sci
2023
MAST1-related mega-corpus-callosum syndrome with central hypogonadism.
Sloboda N et al.·Eur J Med Genet
2023Case report
Cisplatin-mediated activation of glucocorticoid receptor induces platinum resistance via MAST1.
Pan C et al.·Nat Commun
2021
MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation.
Jin L et al.·Cancer Cell
2018
MAST1 variant causes mega-corpus-callosum syndrome with cortical malformations but without cerebellar hypoplasia.
Rodríguez-García ME et al.·Am J Med Genet A
2020Case report
A genetic variant in the MAST1 gene is associated with mega-corpus-callosum syndrome with hypoplastic cerebellar vermis, in a fetus.
Yi S et al.·Mol Genet Genomic Med
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools