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…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 17MIM #615473

Neurodevelopmental disorder with involuntary movementsMIM #617493

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · movement disorder · AD · ClinGen 2019
Definitive · genetic developmental and epileptic encephalopathy · AD · ClinGen 2018
Definitive · developmental and epileptic encephalopathy, 17 · AD · G2P
Strong · neurodevelopmental disorder with involuntary movements · AD · Labcorp Genetics (formerly Invitae)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in GNAO1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

350 rare PASS variants

Rare truncating (LoF)

1 in 7,500

21 rare PASS variants

Rare synonymous (reference)

1 in 100

231 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GNAO1. 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 250	1 in 9,500
South Asian	~43k	1 in 190	≈ 1 in 22,000
Remaining (unassigned)	~30k	1 in 120	none seen
European (Finnish)	~27k	1 in 520	≈ 1 in 26,000
Admixed American	~22k	1 in 190	1 in 3,700
African / African American	~21k	1 in 210	≈ 1 in 6,900
East Asian	~20k	1 in 390	1 in 2,600
Ashkenazi Jewish	~13k	1 in 2,600	none seen
Middle Eastern	~2,884	1 in 290	none seen

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): 6 of 8 coding exons well covered in gnomAD exomes; exons 1, 2 marginal. Genomes: 7 of 8 (exon 2 below).? see exons ↓