Auriculocondylar syndrome 1

Summary

Auriculocondylar syndrome 1 (MONDO:0011234) is a disease caused by GNAI3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: GNAI3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	auriculocondylar syndrome 1
Mondo ID	MONDO:0011234
OMIM	602483
UMLS	C4551996
MedGen	1639644
GARD	0015346
Is cancer (heuristic)	no

Also known as: ARCND1 · Auriculocondylar syndrome 1 · auriculocondylar syndrome caused by mutation in GNAI3 · Auriculocondylar syndrome type 1 · GNAI3 auriculocondylar syndrome

Data availability: 15 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › ear malformation › auriculocondylar syndrome › auriculocondylar syndrome 1

Related subtypes (5): question mark ears, isolated, auriculocondylar syndrome 2, auriculocondylar syndrome 3, auriculocondylar syndrome 4, auriculocondylar syndrome 2B

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

15 retrieved; paginated sample, class counts are floors:

7 pathogenic, 4 uncertain significance, 2 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
31636	NM_006496.4(GNAI3):c.118G>C (p.Gly40Arg)	GNAI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3391816	NM_006496.4(GNAI3):c.645dup (p.Glu216Ter)	GNAI3	Pathogenic	criteria provided, single submitter
450201	NM_006496.4(GNAI3):c.140G>A (p.Ser47Asn)	GNAI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
64691	NM_006496.4(GNAI3):c.141C>A (p.Ser47Arg)	GNAI3	Pathogenic	no assertion criteria provided
209128	NM_001377142.1(PLCB4):c.986A>C (p.Asn329Thr)	PLCB4	Pathogenic	criteria provided, single submitter
31637	NM_001377142.1(PLCB4):c.1904A>G (p.Tyr635Cys)	PLCB4	Pathogenic	criteria provided, single submitter
31639	NM_001377142.1(PLCB4):c.1898G>A (p.Arg633His)	PLCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
31640	NM_001377142.1(PLCB4):c.1897C>T (p.Arg633Cys)	PLCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
31641	NM_001377142.1(PLCB4):c.1984A>C (p.Asn662His)	PLCB4	Pathogenic	criteria provided, single submitter
2663775	NM_006496.4(GNAI3):c.136A>G (p.Lys46Glu)	GNAI3	Likely pathogenic	criteria provided, single submitter
3900657	NM_006496.4(GNAI3):c.805A>T (p.Asn269Tyr)	GNAI3	Likely pathogenic	criteria provided, single submitter
2432198	NM_006496.4(GNAI3):c.145A>G (p.Ile49Val)	GNAI3	Uncertain significance	criteria provided, single submitter
3893135	NM_006496.4(GNAI3):c.725G>C (p.Arg242Pro)	GNAI3	Uncertain significance	criteria provided, single submitter
548497	NM_006496.4(GNAI3):c.146T>C (p.Ile49Thr)	GNAI3	Uncertain significance	criteria provided, multiple submitters, no conflicts
989287	NM_006496.4(GNAI3):c.303+1G>A	GNAI3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GNAI3	Definitive	Autosomal dominant	auriculocondylar syndrome 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNAI3	Orphanet:137888	Auriculocondylar syndrome
PLCB4	Orphanet:137888	Auriculocondylar syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNAI3	HGNC:4387	ENSG00000065135	P08754	Guanine nucleotide-binding protein G(i) subunit alpha-3	gencc,clinvar
PLCB4	HGNC:9059	ENSG00000101333	Q15147	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNAI3	Guanine nucleotide-binding protein G(i) subunit alpha-3	Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
PLCB4	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4	Activated phosphatidylinositol-specific phospholipase C enzymes catalyze the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) involved in G-protein coupled receptor signaling pathways.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNAI3	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
PLCB4	Enzyme (other)	yes	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of esophagus	1
esophagus squamous epithelium	1
tongue squamous epithelium	1
lateral nuclear group of thalamus	1
parotid gland	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNAI3	289	ubiquitous	marker	esophagus squamous epithelium, epithelium of esophagus, tongue squamous epithelium
PLCB4	273	ubiquitous	marker	parotid gland, lateral nuclear group of thalamus, sural nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAI3	2,992
PLCB4	1,595

Intra-cohort edges

A	B	Sources
GNAI3	PLCB4	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAI3	P08754	27

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLCB4	Q15147	86.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Adenylate cyclase inhibitory pathway	1	380.7×	0.013	GNAI3
ADP signalling through P2Y purinoceptor 12	1	248.3×	0.013	GNAI3
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.013	PLCB4
PLC beta mediated events	1	132.8×	0.013	PLCB4
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.013	GNAI3
GPER1 signaling	1	124.1×	0.013	GNAI3
G alpha (z) signalling events	1	116.5×	0.013	GNAI3
Extra-nuclear estrogen signaling	1	85.2×	0.016	GNAI3
G alpha (s) signalling events	1	36.6×	0.033	GNAI3
G alpha (q) signalling events	1	28.7×	0.038	PLCB4
G alpha (i) signalling events	1	19.5×	0.051	GNAI3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phospholipase C-activating endothelin receptor signaling pathway	1	8426.0×	0.001	PLCB4
negative regulation of adenylate cyclase activity	1	702.2×	0.007	GNAI3
GTP metabolic process	1	561.7×	0.007	GNAI3
phosphatidylinositol metabolic process	1	443.5×	0.007	PLCB4
phosphatidylinositol-mediated signaling	1	351.1×	0.007	PLCB4
positive regulation of macroautophagy	1	263.3×	0.008	GNAI3
release of sequestered calcium ion into cytosol	1	172.0×	0.009	PLCB4
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	168.5×	0.009	GNAI3
lipid catabolic process	1	122.1×	0.011	PLCB4
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	109.4×	0.011	GNAI3
cell division	1	23.1×	0.047	GNAI3
G protein-coupled receptor signaling pathway	1	18.1×	0.054	PLCB4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNAI3	1	2
PLCB4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	GNAI3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GNAI3	11	Binding:7, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCB4	3.1.4.11	phosphoinositide phospholipase C

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	GNAI3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	GNAI3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PLCB4
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PLCB4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.