MARK2

Chr 11AD

microtubule affinity regulating kinase 2

Also known as: EMK-1, EMK1, MRD76, PAR-1, Par-1b, Par1b

NCBI Gene: 2011ENSG00000072518UniProt: Q7KZI7

This gene encodes a member of the Par-1 family of serine/threonine protein kinases. The protein is an important regulator of cell polarity in epithelial and neuronal cells, and also controls the stability of microtubules through phosphorylation and inactivation of several microtubule-associating proteins. The protein localizes to cell membranes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 76MIM #621285
AD
135
ClinVar variants
38
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MARK2
⚡
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
38 Pathogenic / Likely Pathogenic· 86 VUS of 135 total submissions

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 5.59
OE 0.05 (0.02–0.16)
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.
4.45Z-score
OE missense 0.43 (0.39–0.49)
212 obs / 488.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.05 (0.02–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.43 (0.39–0.49)
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.0.93
0≤1.21.6
LoF obs/exp: 2 / 40.3Missense obs/exp: 212 / 488.8Syn Z: 0.80

ClinVar Variant Classifications

135 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic16
VUS86
Likely Benign7
Benign4
22
Pathogenic
16
Likely Pathogenic
86
VUS
7
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
13
0
22
Likely Pathogenic
7
5
4
0
16
VUS
17
59
10
0
86
Likely Benign
1
2
2
2
7
Benign
0
0
0
4
4
Total3466296135

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

View in ClinVar →

Protein Context — Lollipop Plot

MARK2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 76

MIM #621285

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway.
Gong M et al.·Am J Hum Genet
2024
Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants.
Hamanaka K et al.·Genome Med
2022
Differential Chemoproteomics Reveals MARK2/3 as Cell Migration-Relevant Targets of the ALK Inhibitor Brigatinib.
Hu Q et al.·Chembiochem
2023
MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKα1/mTOR/HIF-1α signaling pathway.
Natarajan SR et al.·Biochim Biophys Acta Mol Cell Res
2022
Identification of a de Novo MARK2 gene variant in a patient with autism spectrum disorder, epilepsy, and neurodevelopmental delay.
Sun X et al.·Neurogenetics
2025Case report
Lithium Promotes Osteogenesis via Rab11a-Facilitated Exosomal Wnt10a Secretion and β-Catenin Signaling Activation.
Chen C et al.·ACS Appl Mater Interfaces
2024
Identification of MARK2, CCDC71, GATA2, and KLRC3 as candidate diagnostic genes and potential therapeutic targets for repeated implantation failure with antiphospholipid syndrome by integrated bioinformatics analysis and machine learning.
Zhang M et al.·Front Immunol
2023
Satellite Cells in Muscular Dystrophy - Lost in Polarity.
Chang NC et al.·Trends Mol Med
2016Review
Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder.
Khalaf-Nazzal R et al.·Am J Hum Genet
2022
LKB1 signaling and patient survival outcomes in hepatocellular carcinoma.
Nguyen K et al.·Pharmacol Res
2023Review
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