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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

270

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.33

LOEUF· LoF intol.

LOF

Mechanism· predicted

📖

GeneReview available — GSK3B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in GSK3B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 160

426 rare PASS variants

Rare truncating (LoF)

1 in 1,600

55 rare PASS variants

Rare synonymous (reference)

1 in 300

201 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GSK3B. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 240	1 in 1,000
South Asian	~43k	1 in 170	1 in 7,300
Remaining (unassigned)	~30k	1 in 230	1 in 1,400
European (Finnish)	~27k	1 in 490	1 in 3,500
Admixed American	~22k	1 in 190	1 in 4,200
African / African American	~21k	1 in 150	1 in 3,500
East Asian	~20k	1 in 100	1 in 2,100
Ashkenazi Jewish	~13k	1 in 780	none seen
Middle Eastern	~2,884	1 in 170	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 0 of 11 coding exons well covered in gnomAD exomes; exons 1, 2, 3, 4, 5 and 6 more marginal. Genomes: all 11.? see exons ↓