MAPK8IP3

Chr 16AD

mitogen-activated protein kinase 8 interacting protein 3

Also known as: JIP-3, JIP3, JSAP1, NEDBA, SYD2, syd

NCBI Gene: 23162ENSG00000138834UniProt: Q9UPT6

The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction of kinesin I with axonal cargo. Studies of the similar gene in mouse suggested that this protein may interact with, and regulate the activity of numerous protein kinases of the JNK signaling pathway, and thus function as a scaffold protein in neuronal cells. The C. elegans counterpart of this gene is found to regulate synaptic vesicle transport possibly by integrating JNK signaling and kinesin-1 transport. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with or without variable brain abnormalitiesMIM #618443
AD
0
ClinVar variants
0
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— MAPK8IP3
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Gene-Disease Validity (ClinGen)
neurodevelopmental disorder with or without variable brain abnormalities; NEDBA · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: 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
LoF intolerant — likely haploinsufficient
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.
0.15LOEUF
pLI 1.000
Z-score 7.19
OE 0.07 (0.04–0.15)
Highly constrained

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

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.
2.88Z-score
OE missense 0.73 (0.69–0.78)
663 obs / 907.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.07 (0.04–0.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.69–0.78)
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.1.16
0≤1.21.6
LoF obs/exp: 5 / 69.9Missense obs/exp: 663 / 907.5Syn Z: -2.54

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

MAPK8IP3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MAPK8IP3-related intellectual disability with variable brain anomalies

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with or without variable brain abnormalities

MIM #618443

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive Clinical Characteristics, Longitudinal Adaptive Functioning, and Electroencephalogram Activity in MAPK8IP3-Related Neurodevelopmental Disorder.
Sudnawa KK et al.·Clin Genet
2026Natural history
A toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles.
Zhang W et al.·JCI Insight
2025
Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes.
Nomakuchi TT et al.·Am J Med Genet A
2024Cohort
Recurrent de novo MAPK8IP3 variants cause neurological phenotypes.
Iwasawa S et al.·Ann Neurol
2019
De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies.
Platzer K et al.·Am J Hum Genet
2019
Compound heterozygous variants in MAPK8IP3 were detected in severe congenital hypotonia mimicking lethal spinal muscular atrophy.
Kárteszi J et al.·Am J Med Genet A
2023Case report
Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes.
Silvaieh S et al.·Hum Genomics
2023Cohort
ADAM23 haploinsufficiency as a putative oligogenic contributor in an individual with focal epilepsy.
Krenn M et al.·Seizure
2025Case report
Identification of novel targets and pathways to distinguish suicide dependent or independent on depression diagnosis.
Peng S et al.·Sci Rep
2023
Genomic insights and advanced machine learning: characterizing autism spectrum disorder biomarkers and genetic interactions.
Nahas LD et al.·Metab Brain Dis
2024Meta-analysis
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
Neurodevelopmental Disorder With or Without Variable Brain Abnormalities

Personalized Antisense Oligonucleotide for a Single Participant With MAPK8IP3 Neurodevelopmental Disorder With or Without Variable Brain Abnormalities (NEDBA)

ACTIVE NOT RECRUITING
NCT07197294Phase PHASE1, PHASE2n-Lorem FoundationStarted 2025-02-24
nL-MAPK8-001

External Resources

Links to major genomics databases and tools