Otofaciocervical syndrome 2

Summary

Otofaciocervical syndrome 2 (MONDO:0014254) is a disease caused by PAX1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PAX1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	otofaciocervical syndrome 2
Mondo ID	MONDO:0014254
OMIM	615560
UMLS	C5442121
MedGen	1782278
GARD	0016503
Is cancer (heuristic)	no

Also known as: OFC2 · OTFCS2 · otofaciocervical syndrome 2 · otofaciocervical syndrome caused by mutation in PAX1 · otofaciocervical syndrome type 2 · PAX1 otofaciocervical syndrome

Data availability: 22 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › otofaciocervical syndrome › otofaciocervical syndrome 2

Related subtypes (1): otofaciocervical syndrome 1

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

22 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 4 pathogenic, 4 conflicting classifications of pathogenicity, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1171017	NM_001257096.2(PAX1):c.463_465del (p.Asn155del)	PAX1	Pathogenic	no assertion criteria provided
1171018	NM_001257096.2(PAX1):c.439G>C (p.Val147Leu)	PAX1	Pathogenic	no assertion criteria provided
800553	NM_001257096.2(PAX1):c.1104C>A (p.Cys368Ter)	PAX1	Pathogenic	no assertion criteria provided
89026	NM_001257096.2(PAX1):c.497G>T (p.Gly166Val)	PAX1	Pathogenic	criteria provided, single submitter
4526451	NM_001257096.2(PAX1):c.1218del (p.Gly407fs)	PAX1	Likely pathogenic	no assertion criteria provided
4526646	NM_001257096.2(PAX1):c.703G>T (p.Glu235Ter)	PAX1	Likely pathogenic	criteria provided, single submitter
522604	NM_001257096.2(PAX1):c.1169_1173dup (p.Pro392fs)	PAX1	Likely pathogenic	criteria provided, single submitter
1806835	NM_001257096.2(PAX1):c.1212dup (p.Gly405fs)	PAX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2052447	NM_001257096.2(PAX1):c.158C>A (p.Ser53Ter)	PAX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2061950	NM_001257096.2(PAX1):c.509C>A (p.Pro170His)	PAX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2143501	NM_001257096.2(PAX1):c.197dup (p.Ala67fs)	PAX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031025	NM_001257096.2(PAX1):c.95C>T (p.Ala32Val)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031026	NM_001257096.2(PAX1):c.986C>G (p.Thr329Arg)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1213764	NM_001257096.2(PAX1):c.811C>G (p.Pro271Ala)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1403300	NM_001257096.2(PAX1):c.1129G>A (p.Gly377Ser)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1419768	NM_001257096.2(PAX1):c.1175C>G (p.Pro392Arg)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426095	NM_001257096.2(PAX1):c.*204G>A	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806061	NM_001257096.2(PAX1):c.967T>C (p.Trp323Arg)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2179178	NM_001257096.2(PAX1):c.997G>A (p.Ala333Thr)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434579	NM_001257096.2(PAX1):c.1117T>G (p.Ser373Ala)	PAX1	Uncertain significance	criteria provided, single submitter
2584919	NM_001257096.2(PAX1):c.395G>A (p.Arg132Gln)	PAX1	Uncertain significance	criteria provided, single submitter
828160	NM_001257096.2(PAX1):c.1181C>T (p.Pro394Leu)	PAX1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PAX1	Strong	Autosomal recessive	otofaciocervical syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAX1	Orphanet:2792	Otofaciocervical 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
PAX1	HGNC:8615	ENSG00000125813	P15863	Paired box protein Pax-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAX1	Paired box protein Pax-1	This protein is a transcriptional activator.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAX1	Transcription factor	no		Paired_dom, Homeodomain-like_sf, WH-like_DNA-bd_sf

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
male germ line stem cell (sensu Vertebrata) in testis	1
thymus	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAX1	66	tissue_specific	marker	thymus, male germ line stem cell (sensu Vertebrata) in testis, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX1	1,188

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PAX1	P15863	55.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
embryo development ending in birth or egg hatching	1	732.7×	0.005	PAX1
skeletal system development	1	125.8×	0.016	PAX1
transcription by RNA polymerase II	1	70.5×	0.019	PAX1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	PAX1

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
PAX1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	PAX1

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)
PAX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.