GNAI1

Chr 7AD

G protein subunit alpha i1

Also known as: Gi, HG1B, NEDHISB

NCBI Gene: 2770ENSG00000127955UniProt: P63096

Guanine nucleotide binding proteins are heterotrimeric signal-transducing molecules consisting of alpha, beta, and gamma subunits. The alpha subunit binds guanine nucleotide, can hydrolyze GTP, and can interact with other proteins. The protein encoded by this gene represents the alpha subunit of an inhibitory complex. The encoded protein is part of a complex that responds to beta-adrenergic signals by inhibiting adenylate cyclase. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalitiesMIM #619854
AD
150
ClinVar variants
34
Pathogenic / LP
0.91
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GNAI1
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
34 Pathogenic / Likely Pathogenic· 96 VUS of 150 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.38LOEUF
pLI 0.911
Z-score 3.32
OE 0.12 (0.05–0.38)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.63Z-score
OE missense 0.45 (0.38–0.54)
83 obs / 183.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.05–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.45 (0.38–0.54)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.34
0≤1.21.6
LoF obs/exp: 2 / 16.6Missense obs/exp: 83 / 183.1Syn Z: -2.05

ClinVar Variant Classifications

150 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic16
VUS96
Likely Benign11
Benign7
Conflicting2
18
Pathogenic
16
Likely Pathogenic
96
VUS
11
Likely Benign
7
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
5
13
0
18
Likely Pathogenic
0
13
3
0
16
VUS
10
70
16
0
96
Likely Benign
0
4
2
5
11
Benign
0
1
1
5
7
Conflicting
—2
Total10933510150

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

View in ClinVar →

Protein Context — Lollipop Plot

GNAI1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GNAI1-related neurodevelopmental disorder with hypotonia, impaired speech, and behavioural abnormalities

moderate
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
frameshift variantmissense variantinframe deletion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities

MIM #619854

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GNAI1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease.
Solis GP et al.·Cells
2021Case report
Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.
Muir AM et al.·Genet Med
2021
Novel de novo pathogenic variant in the GNAI1 gene as a cause of severe disorders of intellectual development.
Wayhelova M et al.·J Hum Genet
2022Case report
Functional classification of GNAI1 disorder variants in Caenorhabditis elegans uncovers conserved and cell-specific mechanisms of dysfunction.
Salama R et al.·Genetics
2025Functional
A GNAI1 Pathogenic Variant in a Case with GNAO1-Isolated Dystonia: A Modifier of Disease Severity?
Monje MHG et al.·Mov Disord
2024Case report
GNAI1 missense mutations associated with a neurodevelopmental syndrome modify Gα(i1) function.
Fritsche M et al.·Sci Signal
2025
Fibroblast transcriptomics uncovers pathogenic genomic variants in individuals with exome-negative childhood onset epilepsy.
Smal N et al.·Epilepsia
2025
Candidate Gene of NOS3, MMP3, AGT, and AGT1R and Pathway Analyses for Platelet Reactivity and Clinical Outcomes of Repeat Revascularization After First PCI in Chinese Patients.
Zhou S et al.·Cardiovasc Drugs Ther
2023Cohort
G-Protein Signaling in Alzheimer's Disease: Spatial Expression Validation of Semi-supervised Deep Learning-Based Computational Framework.
Zhang DF et al.·J Neurosci
2024
Potential biomarkers of aortic dissection based on expression network analysis.
Feng J et al.·BMC Cardiovasc Disord
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools