GNAI3

Chr 1

G protein subunit alpha i3

Also known as: 87U6, ARCND1, ARCODS, HG1A

NCBI Gene: 2773 ENSG00000065135 UniProt: P08754

Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling pathways. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes an alpha subunit and belongs to the G-alpha family. Mutation in this gene, resulting in a gly40-to-arg substitution, is associated with auriculocondylar syndrome, and shown to affect downstream targets in the G protein-coupled endothelin receptor pathway. [provided by RefSeq, Jun 2012]

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.61

Clinical Summary— GNAI3

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Gene-Disease Validity (ClinGen)

auriculocondylar syndrome · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 50 VUS of 92 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.038

Z-score 2.82

OE 0.31 (0.17–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.79Z-score

OE missense 0.64 (0.55–0.74)

122 obs / 191.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.17–0.61)

0≤0.351.4

Missense OE?0.64 (0.55–0.74)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 6 / 19.4Missense obs/exp: 122 / 191.8Syn Z: 0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGNAI3-related auriculocondylar syndromeOTHERAD

This gene — mechanism propensity

0.6551th %ile

GOF

0.6833th %ile

LOF

0.2969th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

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

DNNovel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 25026904 ↗

ClinVar Variant Classifications

92 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS50

Likely Benign16

Benign8

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	3	0	0	4
VUS	1	48	1	0	50
Likely Benign	0	2	3	11	16
Benign	0	0	6	2	8
Total	3	53	10	13	79

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

View in ClinVar →

4 pathogenic / likely-pathogenic (of 8) ClinVar copy-number / structural variants overlap GNAI3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →