GNAO1

Chr 16AD

G protein subunit alpha o1

Also known as: DEE17, EIEE17, G-ALPHA-o, GNAO, HG1G, NEDIM

NCBI Gene: 2775 ENSG00000087258 UniProt: P09471 OMIM: 139311

The protein encodes the alpha subunit of the Go heterotrimeric G-protein complex, which mediates signal transduction at the cell membrane. Mutations cause early-onset epileptic encephalopathy and neurodevelopmental disorders with involuntary movements through an autosomal dominant inheritance pattern. The gene is highly constrained against loss-of-function variants, and mutations can cause disease through multiple mechanisms depending on the specific variant type.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene represents the alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. Defects in this gene are a cause of early-onset epileptic encephalopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.262 OMIM phenotypes

Clinical Summary— GNAO1

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Gene-Disease Validity (ClinGen)

movement disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

103 unique Pathogenic / Likely Pathogenic· 170 VUS of 587 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GNAO1

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?

0.26LOEUF

pLI 0.990

Z-score 3.73

OE 0.06 (0.02–0.26)

Highly constrained

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

Missense Constraint?

3.19Z-score

OE missense 0.41 (0.34–0.48)

93 obs / 228.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.26)

0≤0.351.4

Missense OE?0.41 (0.34–0.48)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 1 / 18.1Missense obs/exp: 93 / 228.9Syn Z: 0.77

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGNAO1-related epileptic encephalopathyLOFAD

This gene — mechanism propensity

0.4884th %ile

GOF

0.6639th %ile

LOF

0.53top 25%

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

GOFprediction above median · 1 literature citation · 83% of P/LP are missense

LOFLOEUF 0.26

DN1 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

DNExperiments in mice confirmed dominant negative effects of GNAO1 G42R, which impaired numerous motor behaviors.1

GOFMovement disorder in GNAO1 encephalopathy associated with gain-of-function mutations2

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

587 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49

Likely Pathogenic54

VUS170

Likely Benign237

Benign44

Conflicting26

Pathogenic

Likely Pathogenic

170

VUS

237

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	39	3	0	49
Likely Pathogenic	7	46	1	0	54
VUS	4	150	14	2	170
Likely Benign	1	22	92	122	237
Benign	0	1	39	4	44
Conflicting	—				26
Total	19	258	149	128	580

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap GNAO1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →