GNB1

Chr 1AD

G protein subunit beta 1

Also known as: HG2A, MDS, MRD42

NCBI Gene: 2782 ENSG00000078369 UniProt: P62873 OMIM: 139380

The GNB1 protein forms the beta subunit of heterotrimeric G proteins that integrate signals between receptors and effector proteins, regulating both alpha subunits and signal transduction pathways. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder (type 42), with the gene being highly intolerant to loss-of-function variants. Somatic mutations are also associated with acute lymphoblastic leukemia and myelodysplastic syndrome.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.143 OMIM phenotypes

Clinical Summary— GNB1

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Gene-Disease Validity (ClinGen)

intellectual disability, autosomal dominant 42 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

59 unique Pathogenic / Likely Pathogenic· 115 VUS of 400 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GNB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.14LOEUF

pLI 0.999

Z-score 4.21

OE 0.00 (0.00–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.83Z-score

OE missense 0.28 (0.23–0.35)

64 obs / 226.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.14)

0≤0.351.4

Missense OE?0.28 (0.23–0.35)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 0 / 20.6Missense obs/exp: 64 / 226.2Syn Z: 0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGNB1-related severe neurodevelopmental disability, hypotonia, and seizuresGOFAD

This gene — mechanism propensity

0.3594th %ile

GOF

0.4283th %ile

LOF

0.87top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 31% of P/LP variants are LoF · LOEUF 0.14

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFAn activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia.1

LOFThese results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28

Likely Pathogenic31

VUS115

Likely Benign171

Benign22

Conflicting14

Pathogenic

Likely Pathogenic

115

VUS

171

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	15	0	0	28
Likely Pathogenic	5	26	0	0	31
VUS	6	93	15	1	115
Likely Benign	1	10	56	104	171
Benign	0	7	13	2	22
Conflicting	—				14
Total	25	151	84	107	381

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

View in ClinVar →

137 pathogenic / likely-pathogenic (of 167) ClinVar copy-number / structural variants overlap GNB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →