GNAI1

Chr 7AD

G protein subunit alpha i1

Also known as: Gi, HG1B, NEDHISB

NCBI Gene: 2770 ENSG00000127955 UniProt: P63096 OMIM: 139310

The protein is the alpha subunit of an inhibitory G protein complex that responds to beta-adrenergic signals by inhibiting adenylate cyclase. Heterozygous mutations cause a neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities through an autosomal dominant inheritance pattern. The high pLI score (0.91) and low LOEUF score (0.38) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.381 OMIM phenotype

Clinical Summary— GNAI1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · 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 0.91). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 94 VUS of 149 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GNAI1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.12 (0.05–0.38)

0≤0.351.4

Missense OE?0.45 (0.38–0.54)

0≤0.61.4

Synonymous OE?1.34

0≤1.21.6

LoF obs/exp: 2 / 16.6Missense obs/exp: 83 / 183.1Syn Z: -2.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateGNAI1-related neurodevelopmental disorder with hypotonia, impaired speech, and behavioural abnormalitiesOTHERAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.6639th %ile

LOF

0.48top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). 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 · 95% of P/LP are missense

LOFLOEUF 0.38

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.

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

149 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic14

VUS94

Likely Benign14

Benign6

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	6	0	0	6
Likely Pathogenic	0	13	1	0	14
VUS	14	76	4	0	94
Likely Benign	0	5	3	6	14
Benign	0	0	1	5	6
Conflicting	—				3
Total	14	100	9	11	137

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap GNAI1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →