GSK3A

Chr 19

glycogen synthase kinase 3 alpha

NCBI Gene: 2931 ENSG00000105723 UniProt: P49840 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

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]

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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.13

LOEUF· LoF intol.

LOF

Mechanism· predicted

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 OE?0.00 (0.00–0.13)

0≤0.351.4

Missense OE?0.42 (0.36–0.50)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 0 / 23.3Missense obs/exp: 103 / 244.6Syn Z: 1.04

Background carrier burden — how many people carry a rare variant somewhere in GSK3A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 97

654 rare PASS variants

Rare truncating (LoF)

1 in 1,100

88 rare PASS variants

Rare synonymous (reference)

1 in 140

315 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GSK3A. 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 110	1 in 1,700
South Asian	~43k	1 in 84	1 in 480
Remaining (unassigned)	~30k	1 in 110	1 in 1,100
European (Finnish)	~27k	1 in 310	≈ 1 in 5,900
Admixed American	~22k	1 in 83	1 in 670
African / African American	~21k	1 in 87	1 in 2,500
East Asian	~20k	1 in 100	1 in 1,700
Ashkenazi Jewish	~13k	1 in 330	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 92	≈ 1 in 2,800

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): 9 of 11 coding exons well covered in gnomAD exomes; exons 1, 10 marginal. Genomes: all 11.? see exons ↓