Auriculocondylar syndrome 2

Summary

Auriculocondylar syndrome 2 (MONDO:0013845) is a disease caused by PLCB4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PLCB4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 131

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	auriculocondylar syndrome 2
Mondo ID	MONDO:0013845
OMIM	614669
UMLS	C3553404
MedGen	766318
GARD	0015831
Is cancer (heuristic)	no

Also known as: ARCND2 · Auriculocondylar syndrome 2 · auriculocondylar syndrome caused by mutation in PLCB4 · Auriculocondylar syndrome type 2 · PLCB4 auriculocondylar syndrome

Data availability: 131 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 2

Related subtypes (5): auriculocondylar syndrome 1, question mark ears, isolated, 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

131 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 42 benign, 11 pathogenic, 10 benign/likely benign, 7 conflicting classifications of pathogenicity, 6 likely benign, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1706453	NM_001377142.1(PLCB4):c.2814+1G>C	PLCB4	Pathogenic	criteria provided, single submitter
31637	NM_001377142.1(PLCB4):c.1904A>G (p.Tyr635Cys)	PLCB4	Pathogenic	criteria provided, single submitter
31638	NM_001377142.1(PLCB4):c.986A>G (p.Asn329Ser)	PLCB4	Pathogenic	no assertion criteria provided
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
635078	NM_001377142.1(PLCB4):c.1924G>A (p.Asp642Asn)	PLCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
64692	NM_001377142.1(PLCB4):c.1898G>T (p.Arg633Leu)	PLCB4	Pathogenic	no assertion criteria provided
64693	NM_001377142.1(PLCB4):c.1073A>T (p.Glu358Val)	PLCB4	Pathogenic	no assertion criteria provided
64694	NM_001377142.1(PLCB4):c.1078G>A (p.Asp360Asn)	PLCB4	Pathogenic	no assertion criteria provided
64695	NM_001377142.1(PLCB4):c.1079A>T (p.Asp360Val)	PLCB4	Pathogenic	no assertion criteria provided
64696	NM_001377142.1(PLCB4):c.1648-279_2051+1546del	PLCB4	Pathogenic	no assertion criteria provided
1030923	NM_001377142.1(PLCB4):c.1124A>G (p.His375Arg)	PLCB4	Likely pathogenic	criteria provided, single submitter
3382174	NM_001377142.1(PLCB4):c.1057G>A (p.Gly353Ser)	PLCB4	Likely pathogenic	criteria provided, single submitter
3777145	NM_001377142.1(PLCB4):c.1732T>C (p.Ser578Pro)	PLCB4	Likely pathogenic	criteria provided, single submitter
4294389	NM_001377142.1(PLCB4):c.1080C>G (p.Asp360Glu)	PLCB4	Likely pathogenic	criteria provided, single submitter
1706548	NM_001377142.1(PLCB4):c.1015G>A (p.Gly339Arg)	PLCB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339557	NM_001377142.1(PLCB4):c.833A>T (p.Asp278Val)	PLCB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339567	NM_001377142.1(PLCB4):c.1738A>G (p.Met580Val)	PLCB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339570	NM_001377142.1(PLCB4):c.1885C>T (p.Arg629Trp)	PLCB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4686461	NM_001377142.1(PLCB4):c.1751C>A (p.Ala584Asp)	PLCB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897770	NM_001377142.1(PLCB4):c.3133G>T (p.Ala1045Ser)	PLCB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897772	NM_001377142.1(PLCB4):c.3210C>G (p.His1070Gln)	PLCB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299329	NM_001377142.1(PLCB4):c.1223T>C (p.Phe408Ser)	PLCB4	Uncertain significance	criteria provided, single submitter
1675192	NM_001377142.1(PLCB4):c.687-3C>G	PLCB4	Uncertain significance	criteria provided, single submitter
1687451	NM_001377142.1(PLCB4):c.2050G>A (p.Gly684Arg)	PLCB4	Uncertain significance	criteria provided, single submitter
3234864	NM_001377142.1(PLCB4):c.2681A>C (p.Lys894Thr)	PLCB4	Uncertain significance	criteria provided, single submitter
3236137	NM_001377142.1(PLCB4):c.962A>T (p.His321Leu)	PLCB4	Uncertain significance	criteria provided, single submitter
339556	NM_001377142.1(PLCB4):c.535G>A (p.Glu179Lys)	PLCB4	Uncertain significance	criteria provided, single submitter
339558	NM_001377142.1(PLCB4):c.854-13C>T	PLCB4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
PLCB4	Strong	Autosomal dominant	auriculocondylar syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLCB4	Orphanet:137888	Auriculocondylar syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLCB4	HGNC:9059	ENSG00000101333	Q15147	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 0 · Druggable fraction: 1.0

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	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
PLCB4	273	ubiquitous	marker	parotid gland, lateral nuclear group of thalamus, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLCB4	1,595

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLCB4	Q15147	86.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.006	PLCB4
PLC beta mediated events	1	265.6×	0.006	PLCB4
G alpha (q) signalling events	1	57.4×	0.017	PLCB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	16852.0×	4e-04	PLCB4
phosphatidylinositol metabolic process	1	887.0×	0.003	PLCB4
phosphatidylinositol-mediated signaling	1	702.2×	0.003	PLCB4
release of sequestered calcium ion into cytosol	1	343.9×	0.004	PLCB4
lipid catabolic process	1	244.2×	0.005	PLCB4
G protein-coupled receptor signaling pathway	1	36.2×	0.028	PLCB4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLCB4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCB4	3.1.4.11	phosphoinositide phospholipase C

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
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.