GSK3A

Chr 19

glycogen synthase kinase 3 alpha

NCBI Gene: 2931 ENSG00000105723 UniProt: P49840

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.

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— GSK3A

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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.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 34 VUS of 46 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

This gene — mechanism propensity

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

46 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS34

Likely Benign1

Benign1

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	1	33	0	0	34
Likely Benign	0	0	0	1	1
Benign	0	0	0	1	1
Total	1	33	1	2	37

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap GSK3A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →