GSK3A

Chr 19

glycogen synthase kinase 3 alpha

NCBI Gene: 2931ENSG00000105723UniProt: P49840

This gene encodes a multifunctional Ser/Thr protein kinase that is implicated in the control of several regulatory proteins including glycogen synthase, and transcription factors, such as JUN. It also plays a role in the WNT and PI3K signaling pathways, as well as regulates the production of beta-amyloid peptides associated with Alzheimer's disease. [provided by RefSeq, Oct 2011]

50
ClinVar variants
14
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
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 Pathogenic / Likely Pathogenic· 34 VUS of 50 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.
0.13LOEUF
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?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.
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?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.0.00 (0.00–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.42 (0.36–0.50)
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.0.87
0≤1.21.6
LoF obs/exp: 0 / 23.3Missense obs/exp: 103 / 244.6Syn Z: 1.04

ClinVar Variant Classifications

50 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic1
VUS34
Likely Benign1
Benign1
13
Pathogenic
1
Likely Pathogenic
34
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
32
1
0
34
Likely Benign
0
0
0
1
1
Benign
0
0
0
1
1
Total13215250

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
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
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
Quantitative phosphoproteomics reveals GSK3A substrate network is involved in the cryodamage of sperm motility.
Wang J et al.·Biosci Rep
2021
CETSA-MS-based target profiling of anti-aging natural compound quercetin.
Bai L et al.·Eur J Med Chem
2024
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
QM107, a novel CD148 (RTP Type J) activating peptide therapy for treating neovascular age-related macular degeneration.
Arokiasamy S et al.·Br J Pharmacol
2025
Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations.
O'Connell AE et al.·Am J Hum Genet
2018
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
A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220.
Hou P et al.·Cancer Res
2017
PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia.
Curtiss BM et al.·Leukemia
2022
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