MAST3

Chr 19AD

microtubule associated serine/threonine kinase 3

Also known as: DEE108

NCBI Gene: 23031 ENSG00000099308 UniProt: O60307 OMIM: 612258

This gene encodes a serine/threonine kinase that regulates cytoskeleton organization and intracellular signal transduction. Mutations cause developmental and epileptic encephalopathy 108, inherited in an autosomal dominant pattern, predominantly through loss-of-function mechanisms. The gene shows extreme intolerance to loss-of-function variants, consistent with haploinsufficiency being pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, Mechanism

Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in cytoskeleton organization and intracellular signal transduction. Predicted to be located in cytoplasm. Implicated in developmental and epileptic encephalopathy 108. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.221 OMIM phenotype

Clinical Summary— MAST3

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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

9 unique Pathogenic / Likely Pathogenic· 208 VUS of 325 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?

0.22LOEUF

pLI 1.000

Z-score 5.97

OE 0.11 (0.06–0.22)

Highly constrained

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

Missense Constraint?

4.14Z-score

OE missense 0.60 (0.56–0.65)

510 obs / 849.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.22)

0≤0.351.4

Missense OE?0.60 (0.56–0.65)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 6 / 52.8Missense obs/exp: 510 / 849.2Syn Z: 0.86

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateMAST3-related developmental and epileptic encephalopathyGOFAD

This gene — mechanism propensity

0.5180th %ile

GOF

0.5954th %ile

LOF

0.70top 10%

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 · LOEUF 0.22

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

GOFThese findings suggest the patient-specific variants may confer MAST3 gain-of-function.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 34185323 ↗

ClinVar Variant Classifications

325 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic4

VUS208

Likely Benign54

Benign8

Conflicting1

Pathogenic

Likely Pathogenic

208

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	0	0	5
Likely Pathogenic	0	4	0	0	4
VUS	12	190	5	1	208
Likely Benign	0	37	3	14	54
Benign	0	3	2	3	8
Conflicting	—				1
Total	12	239	10	18	280

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap MAST3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →