GeneBe

GNAI3

protein-coding

G protein subunit alpha i3, the group of G protein subunits alpha, group i

Gene summary

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]

MANE transcript

NM_006496.4

Inheritance

AD

ClinVar variants

P:8U:67B:22

Top phenotype

Auriculocondylar syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr1:109,548,615-109,600,195

External References & Databases

Ensembl (ENSG00000065135)NCBI Gene (2773)OMIM (139370)HGNC:4387GenCCUniProt (P08754)AlphaFoldClinVar (GNAI3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~51.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

auriculocondylar syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000107

Submitter: Orphanet

auriculocondylar syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011234

Submitter: G2P

auriculocondylar syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011234

Submitter: Labcorp Genetics (formerly Invitae)

auriculocondylar syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011234

Submitter: PanelApp Australia

auriculocondylar syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0000107

Submitter: ClinGen

GNAI3 was first reported in relation to autosomal dominant auriculocondylar syndrome in 2012 (Rieder et al., PMID: 22560091). This condition is characterized by distinctive auricular malformations, most notably “question mark ear,” defined as a spectrum of congenital auricular clefting in which there is partial to complete separation between the ascending helix and the lobule, resulting in a configuration resembling a question mark. Individuals can also have ear hypoplasia, severe micrognathia/mandibular hypoplasia; other mandibular anomalies; and facial dysmorphisms (such as round face, cleft palate, and facial asymmetry). 9 variants (all missense) that have been reported in 19 probands in 9 publications (PMIDs: 22560091, 23315542, 25026904, 33723370, 34789173, 35170830, 36797717, 38177409, 39014351) and in ClinVar (Athena Diagnostics (SCV002817290.1); GeneDx (SCV005325112.1, SCV000618754.3); LabCorp Genetics (SCV004434179.3); and Medicover Genetics (SCV005387608.1) internal data) are included in this curation. Variants cluster between residues 40-48. Some variants, such as p.Gly40Arg, p.Gly40Val, and p.Ser47Asn, have been recurrently found in affected probands. The mechanism of pathogenicity appears to be dominant negative (PMID: 25026904). Experimental evidence (a mouse model) was evaluated (PMID: 23236180) but not scored since it lacked a specific craniofacial phenotype. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Craniofacial GCEP on the meeting date 5/21/2026 (SOP Version 12).

auriculocondylar syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011234

Submitter: Illumina

auriculocondylar syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011234

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Auriculocondylar syndrome 1AD

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22560091; 23315542Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNAI3 variants in ClinVar

5 Conditions Cataloged
not providedTotal: 46
Inborn genetic diseasesTotal: 32
GNAI3-related disorderTotal: 14
not specifiedTotal: 14
Auriculocondylar syndrome 1Total: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006496.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
16
clinvar
1
clinvar
 18
missense
1
clinvar
6
clinvar
59
clinvar
5
clinvar
 71
nonsense
2
clinvar
 2
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total266721197
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006496.4RefSeqNP_006487.18MANE Select
ENST00000369851.7EnsemblENSP00000358867.48MANE Select
ENST00000879740.1EnsemblENSP00000549799.18Standard
ENST00000879740.2EnsemblENSP00000549799.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Platelet activation - Homo sapiens (human)
  • Relaxin signaling pathway - Homo sapiens (human)
  • Regulation of lipolysis in adipocytes - Homo sapiens (human)
  • Oxytocin signaling pathway - Homo sapiens (human)
  • Pertussis - Homo sapiens (human)

Biological Process

  • protein folding
  • vesicle fusion
  • cell cycle
  • G protein-coupled receptor signaling pathway
  • adenylate cyclase-modulating G protein-coupled receptor signaling pathway

Molecular Function

  • G protein-coupled receptor binding
  • GTPase activity
  • protein binding
  • GTP binding
  • GDP binding

Cellular Component

  • Golgi membrane
  • nucleus
  • nucleolus
  • cytoplasm
  • lysosomal membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000369851
Coding exons
8
Length
45743
Individuals with no LoFs
125728
Homozygous LoFs
0
Heterozygous LoFs
18
Defined
125746
p
0.0000716
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.791221920.6360.000009382347
Missense (PolyPhen)3875.490.50338956
Synonymous0.3356467.50.9480.00000322642
Loss of Function2.82619.40.3090.00000108238

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.000120.00012rare
South Asian0.0000980.000098rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:8774883, PubMed:18434541, PubMed:19478087). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (PubMed:19478087). Stimulates the activity of receptor-regulated K(+) channels (PubMed:2535845). The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division (PubMed:17635935). {ECO:0000269|PubMed:17635935, ECO:0000269|PubMed:18434541, ECO:0000269|PubMed:2535845, ECO:0000269|PubMed:8774883}.;
Disease
DISEASE: Auriculocondylar syndrome 1 (ARCND1) [MIM:602483]: An autosomal dominant craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia. {ECO:0000269|PubMed:22560091}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.156

Intolerance Scores

LoFtool
0.449
RVIS EVS
-0.25
RVIS percentile EVS
35.42

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.903

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.