GSK3B

Chr 3

glycogen synthase kinase 3 beta

NCBI Gene: 2932 ENSG00000082701 UniProt: P49841 OMIM: 605004

The encoded protein is a serine-threonine kinase that regulates glucose homeostasis, Wnt signaling, and multiple cellular processes including transcription factor activity and microtubule dynamics through phosphorylation of diverse substrates. Mutations in GSK3B cause autosomal dominant neurodevelopmental disorders with intellectual disability and behavioral abnormalities. This gene is highly constrained against loss-of-function variants (pLI 0.96), indicating that haploinsufficiency is likely not tolerated in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a serine-threonine kinase belonging to the glycogen synthase kinase subfamily. It is a negative regulator of glucose homeostasis and is involved in energy metabolism, inflammation, ER-stress, mitochondrial dysfunction, and apoptotic pathways. Defects in this gene have been associated with Parkinson disease and Alzheimer disease. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.33

Clinical Summary— GSK3B

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 32 VUS of 76 total submissions

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GeneReview available — GSK3B

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.956

Z-score 4.14

OE 0.15 (0.07–0.33)

Highly constrained

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

Missense Constraint?

2.80Z-score

OE missense 0.49 (0.42–0.57)

117 obs / 238.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.33)

0≤0.351.4

Missense OE?0.49 (0.42–0.57)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 4 / 27.4Missense obs/exp: 117 / 238.6Syn Z: 0.61

This gene — mechanism propensity

0.3991th %ile

GOF

0.4283th %ile

LOF

0.74top 10%

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

LOFprediction above median · LOEUF 0.33

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

76 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS32

Likely Benign2

Benign22

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	1	0	0	0	1
VUS	9	21	1	1	32
Likely Benign	0	0	1	1	2
Benign	0	0	18	4	22
Total	12	21	20	6	59

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap GSK3B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →