GSK3A

Chr 19

glycogen synthase kinase 3 alpha

NCBI Gene: 2931ENSG00000105723UniProt: P49840OMIM: 606784

The protein encoded by this gene is a constitutively active serine/threonine kinase that regulates glucose homeostasis by phosphorylating and inhibiting glycogen synthase, controls Wnt signaling through beta-catenin phosphorylation, and is essential for neuronal polarity and axon outgrowth. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay, though the specific phenotypic spectrum is still being characterized. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.13), indicating that complete loss of function is likely incompatible with normal development.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismLOEUF 0.13
Clinical Summary— GSK3A
⚡
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
14 unique Pathogenic / Likely Pathogenic· 35 VUS of 60 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
0.13LOEUF
pLI 1.000
Z-score 4.47
OE 0.00 (0.00–0.13)
Highly constrained

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

Missense Constraint
3.22Z-score
OE missense 0.42 (0.36–0.50)
103 obs / 244.6 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.13)
0≤0.351.4
Missense OE0.42 (0.36–0.50)
0≤0.61.4
Synonymous OE0.87
0≤1.21.6
LoF obs/exp: 0 / 23.3Missense obs/exp: 103 / 244.6Syn Z: 1.04
DN
0.2598th %ile
GOF
0.2796th %ile
LOF
0.86top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.13

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

ClinVar Variant Classifications

60 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic1
VUS35
Likely Benign1
Benign1
13
Pathogenic
1
Likely Pathogenic
35
VUS
1
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
13
0
13
Likely Pathogenic
0
0
1
0
1
VUS
1
33
1
0
35
Likely Benign
0
0
0
1
1
Benign
0
0
0
1
1
Total13315251

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

View in ClinVar →

Protein Context — Lollipop Plot

GSK3A · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
GSK3A promotes human adenovirus replication and phosphorylates viral L4-22K protein.
Lin Y et al.·Life Sci Alliance
2025
Quantitative phosphoproteomics reveals GSK3A substrate network is involved in the cryodamage of sperm motility.
Wang J et al.·Biosci Rep
2021
The ubiquitin ligase HUWE1 enhances WNT signaling by antagonizing destruction complex-mediated β-catenin degradation and through a mechanism independent of changes in β-catenin abundance.
McKenna JK et al.·PLoS Genet
2025Functional
Differential impact of hepatitis delta virus replication and expression of viral antigens on the cellular kinome profile.
Thiyagarajah K et al.·Cell Commun Signal
2025
Deciphering pathogenic mechanisms of BDCPP exposure in endometrial cancer progression via an integrated approach combining network toxicology, machine learning, and molecular docking.
Wang Z et al.·Int J Surg
2026Functional
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients