PAX1

Summary

PAX1 (paired box 1, HGNC:8615) is a protein-coding gene on chromosome 20p11.22, encoding Paired box protein Pax-1 (P15863). This protein is a transcriptional activator.

This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. This gene plays a role in pattern formation during embryogenesis and may be essential for development of the vertebral column. This gene is silenced by methylation in ovarian and cervical cancers and may be a tumor suppressor gene. Mutations in this gene are also associated with vertebral malformations.

Source: NCBI Gene 5075 — RefSeq curated summary.

At a glance

• Gene–disease (curated): otofaciocervical syndrome 2 (Definitive, ClinGen)
• GWAS associations: 23
• Clinical variants (ClinVar): 519 total — 14 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 41
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Transcription factor: yes — 99 downstream targets (CollecTRI)
• MANE Select transcript: NM_001257096

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8615
Approved symbol	PAX1
Name	paired box 1
Location	20p11.22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125813
Ensembl biotype	protein_coding
OMIM	167411
Entrez	5075

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000398485, ENST00000444366, ENST00000485038, ENST00000613128

RefSeq mRNA: 2 — MANE Select: NM_001257096 NM_001257096, NM_006192

CCDS: CCDS13146, CCDS74709

Canonical transcript exons

ENST00000613128 — 5 exons

Exon	Start	End
ENSE00000859424	21706438	21707067
ENSE00000859426	21709222	21709444
ENSE00003633605	21708558	21708700
ENSE00003741077	21714471	21718481
ENSE00003919701	21705664	21705998

Expression profiles

Bgee: expression breadth broad, 66 present calls, max score 82.05.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6221 / max 199.1491, expressed in 74 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183806	0.3979	49
183805	0.1906	45
183807	0.0176	8
183808	0.0160	8

Top tissues by expression

265 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	82.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.04	gold quality
tibia	UBERON:0000979	77.15	gold quality
oral cavity	UBERON:0000167	77.10	gold quality
buccal mucosa cell	CL:0002336	73.47	silver quality
tonsil	UBERON:0002372	70.68	gold quality
amniotic fluid	UBERON:0000173	69.75	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	67.10	gold quality
superior surface of tongue	UBERON:0007371	65.87	gold quality
mucosa of paranasal sinus	UBERON:0005030	65.28	silver quality
sperm	CL:0000019	63.97	gold quality
bronchial epithelial cell	CL:0002328	63.78	silver quality
male germ cell	CL:0000015	63.52	gold quality
epithelium of bronchus	UBERON:0002031	63.39	silver quality
bronchus	UBERON:0002185	63.12	silver quality
tongue	UBERON:0001723	62.22	silver quality
hair follicle	UBERON:0002073	61.99	gold quality
nasal cavity mucosa	UBERON:0001826	61.83	gold quality
epithelial cell of pancreas	CL:0000083	61.82	gold quality
cerebellar vermis	UBERON:0004720	61.20	gold quality
tendon of biceps brachii	UBERON:0008188	61.07	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	59.40	gold quality
upper leg skin	UBERON:0004262	59.21	silver quality
body of tongue	UBERON:0011876	59.18	silver quality
biceps brachii	UBERON:0001507	58.54	gold quality
pharyngeal mucosa	UBERON:0000355	58.29	silver quality
esophagus squamous epithelium	UBERON:0006920	58.07	silver quality
tongue squamous epithelium	UBERON:0006919	58.06	gold quality
epithelium of nasopharynx	UBERON:0001951	57.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.38	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	774.72
E-ANND-3	no	2.75

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

99 targets.

Target	Regulation
ABCB1
ABCC1
ABL1
BAD
BCR
BDNF
BGLAP
BIRC3
BIRC5
CA9
CAT
CCR6
CD74
CDK1
CDKN1A
CDKN2A
CDKN3
CKM
CLC
CNTN2
CTNNB1
CXCL8
DLD
DSC3
EIF4E
EVPL
EWSR1
EYA1
FASLG
FLNA

JASPAR motifs

Motif	Name	Family
MA0779.1	PAX1	Paired domain only
MA0779.2	PAX1	Paired domain only

JASPAR matrix evidence (PMIDs): PMID:19132093

Upstream regulators (CollecTRI, top): DDIT3, ETS1, ETS2, FOXC2, HOXA5, HR, JUN, NFKB, NFKBIA, NKX2-2, PAX1, SP1, TBX10, THRB, TP53

miRNA regulators (miRDB)

109 targeting PAX1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-149-3P	99.72	68.22	3963

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 37)

• There was a significant reduction in PAX1 expression in fetuses with the Jarcho-Levin syndrome. (PMID:12833407)
• No mutations were identified in the PAX1 and MEOX1 exons or flanking intronic sequences, excluding them as likely causative genes for diaphanospondylodysostosis (PMID:17764081)
• PAX1 hypermethylation is associated with cervical cancer. (PMID:20442585)
• We identified PAX1 as a novel disease-causing gene for otofaciocervical syndrome and show that the pooling of DNA from affected individuals can reduce the number of putative disease-causing homozygous variants in consanguineous families. (PMID:23851939)
• Testing PAX1 DNA methylation using oral swabs is a promising method for oral cancer detection. Combined assessments regarding betel nut consumption and DNA methylation can improve OSCC screening (PMID:23907469)
• Cervical adenocarcinoma cells carry aberrantly high methylation rates of PAX1, commonly methylated in squamous cell carcinomas. (PMID:24407576)
• PAX1 methylation is associated with high-grade squamous intraepithelial lesions. (PMID:24568514)
• PAX1 and SOX1 DNA methylation correlate with a cervical intraepithelial neoplasia diagnosis. (PMID:24799352)
• PAX1 methylation is associated with cervical cancer. (PMID:24844223)
• analysis of a PAX1 enhancer locus that is associated with susceptibility to idiopathic scoliosis in females (PMID:25784220)
• meta-analysis support the utility of PAX1 methylation as an auxiliary biomarker in cervical cancer screening (PMID:26234429)
• Hypermethylation of PAX1 gene may be highly associated with the development of cervical cancer. (PMID:26552048)
• PAX1 methylation hallmarks a potential diagnostic value for cervical cancer screening in Asians (PMID:26642709)
• Paired boxed gene 1 protein expression is a potential histopathology biomarker for the differential diagnosis of malignant and premalignant endometrial lesions. Paired boxed gene 1 is also a potential prognostic marker in cases of endometrial carcinoma. (PMID:27226215)
• conclude that hypermethylated ZNF582 and PAX1 are effective biomarkers for the detection of oral dysplasia and oral cancer and for the prediction of oral cancer recurrence (PMID:27865370)
• DNA methylation status of PAX1 showed a relatively good sensitivity and specificity for the detection of ESOPHAGEAL SQUAMOUS CELL CARCINOMA. (PMID:28241446)
• PAX1 gene methylation was associated with the transition of CIN I to CIN II/III and CIN II/III to cervical cancer, so that it could be an auxiliary biomarker to estimate the risk of CIN progress. (PMID:28472814)
• A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency has been described in a consanguineous family. (PMID:28657137)
• Hypermethylated ZNF582 and PAX1 genes in oral epithelial cells collected by mouth rinse are effective biomarkers for the detection of oral dysplasia and oral cancer. (PMID:28960639)
• The association between PAX1 and the susceptibility of AIS was successfully replicated in the Chinese population (PMID:29095406)
• Hypermethylated ZNF582 and PAX1 genes in the oral scrapings collected from adjacent normal oral mucosal sites rather than cancer sites are associated with aggressive progression and poor prognosis of OSCC (PMID:29224816)
• Here we report a third family of OTFCS2 phenotype wherein whole exome sequencing identified a novel homozygous small insertion in PAX1 as the underlying genetic cause. (PMID:29681087)
• Both PAX1 rs17861031 and rs6137473 were significantly associated with AIS and different PUMC classifications of AIS in a northern Chinese Han population. (PMID:30572100)
• Paired Box-1 (PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer. (PMID:31235851)
• Data found a strong association between PAX1 methylation and the development of cervical cancer. Hypermethylation of distinct CpG sites may induce HSIL transformation into invasive cervical cancer in both Uyghur and Han patients suggesting the existence of ethnic differences in the genetic susceptibility to cervical cancer. Also, PAX1 methylation and HPV infection exhibited synergistic effects on cervical tumorigenesis. (PMID:31589957)
• The methylation levels ofPAX1, SOX1 and ZNF582 genes were all higher in cancer tissues. (PMID:31629253)
• PAX1 is essential for development and function of the human thymus. (PMID:32111619)
• Temporal and spatial expression of Sox9, Pax1, TGF-beta1 and type I and II collagen in human intervertebral disc development. (PMID:32201238)
• Hypermethylated PAX1 and ZNF582 genes in the tissue sample are associated with aggressive progression of oral squamous cell carcinoma. (PMID:32428271)
• The application value of PAX1 and ZNF582 gene methylation in high grade intraepithelial lesion and cervical cancer. (PMID:32514824)
• Real time quantitative methylation detection of PAX1 gene in cervical cancer screening. (PMID:32616628)
• SOX1 and PAX1 Are Hypermethylated in Cervical Adenocarcinoma and Associated with Better Prognosis. (PMID:33376722)
• Aberrant Epigenetic Alteration of PAX1 Expression Contributes to Parathyroid Tumorigenesis. (PMID:34453169)
• PAX1 expression in thymic epithelial neoplasms and morphologic mimics. (PMID:37776957)
• High-grade cervical lesions diagnosed by JAM3/PAX1 methylation in high-risk human papillomavirus-infected patients. (PMID:38448375)
• PAX1 represses canonical Wnt signaling pathway and plays dual roles during endoderm differentiation. (PMID:38664733)
• Relationship between p16/ki67 immunoscores and PAX1/ZNF582 methylation status in precancerous and cancerous cervical lesions in high-risk HPV-positive women. (PMID:39304838)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pax1a	ENSDARG00000008203
danio_rerio	pax1b	ENSDARG00000073814
mus_musculus	Pax1	ENSMUSG00000037034
rattus_norvegicus	Pax1	ENSRNOG00000024882
drosophila_melanogaster	Poxm	FBGN0003129

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Paired box protein Pax-1 — P15863 (reviewed: P15863)

Alternative names: HuP48

All UniProt accessions (2): P15863, A0A087WXV5

UniProt curated annotations — full annotation on UniProt →

Function. This protein is a transcriptional activator. It may play a role in the formation of segmented structures of the embryo. May play an important role in the normal development of the vertebral column.

Subcellular location. Nucleus.

Disease relevance. Otofaciocervical syndrome 2, with T-cell deficiency (OTFCS2) [MIM:615560] An autosomal recessive disorder characterized by facial dysmorphism, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies including vertebral defects, low-set clavicles, winged scapulae, sloping shoulders, and mild intellectual disability. Some patients also exhibit altered thymus development with T-cell immunodeficiency. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
P15863-1	1	yes
P15863-2	2
P15863-3	3

RefSeq proteins (2): NP_001244025, NP_006183 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001523	Paired_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR043182	PAIRED_DNA-bd_site	Conserved_site
IPR043565	PAX_fam	Family

Pfam: PF00292

UniProt features (13 total): sequence variant 5, region of interest 4, splice variant 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15863-F1	55.21	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 201 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GCANCTGNY_MYOD_Q6, RACCACAR_AML_Q6, CAGCTG_AP4_Q5, AML_Q6, ATF1_Q6, SU_THYMUS, GOBP_EMBRYO_DEVELOPMENT, RASHI_RESPONSE_TO_IONIZING_RADIATION_5, TGGAAA_NFAT_Q4_01, OSF2_Q6, chr20p11, HEB_Q6

GO Biological Process (15): skeletal system development (GO:0001501), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), embryo development ending in birth or egg hatching (GO:0009792), somitogenesis (GO:0001756), regulation of DNA-templated transcription (GO:0006355), pattern specification process (GO:0007389), cell population proliferation (GO:0008283), CD4-positive, alpha-beta T cell differentiation (GO:0043367), CD8-positive, alpha-beta T cell differentiation (GO:0043374), positive regulation of transcription by RNA polymerase II (GO:0045944), thymus development (GO:0048538), parathyroid gland development (GO:0060017), bone morphogenesis (GO:0060349), sclerotome development (GO:0061056)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
somite development	2
alpha-beta T cell differentiation	2
regulation of transcription by RNA polymerase II	2
gland development	2
system development	1
regulation of DNA-templated transcription	1
embryo development	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
multicellular organism development	1
multicellular organismal process	1
cellular process	1
CD4-positive, alpha-beta T cell activation	1
CD8-positive, alpha-beta T cell activation	1
positive regulation of DNA-templated transcription	1
hematopoietic or lymphoid organ development	1
endocrine system development	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
mesenchyme development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAX1	MEOX1	P50221	799
PAX1	ZNF582	Q96NG8	776
PAX1	EYA1	Q99502	768
PAX1	SCX	Q7RTU7	713
PAX1	TCF15	Q12870	689
PAX1	MSX1	P28360	671
PAX1	NKX3-2	P78367	670
PAX1	MESP2	Q0VG99	656
PAX1	TGFA	P01135	612
PAX1	HOXA3	O43365	610
PAX1	UNCX	A6NJT0	606
PAX1	SOX1	O00570	604
PAX1	FOXN1	O15353	593
PAX1	GCM2	O75603	588
PAX1	FOXA2	Q9Y261	579

IntAct

3 interactions, top by confidence:

A	B	Type	Score
PAX1	MEOX1	psi-mi:“MI:0407”(direct interaction)	0.530
MEOX1	PAX1	psi-mi:“MI:0915”(physical association)	0.530

BioGRID (5): PAX1 (Affinity Capture-MS), MEOX1 (Two-hybrid), MEOX2 (Two-hybrid), PAX1 (Reconstituted Complex), PAX1 (Reconstituted Complex)

ESM2 similar proteins: A0A2Z4LIS9, A2CE44, A6NFI3, E9PZZ1, O95201, P09066, P15863, P19622, P22091, P46099, P49640, P70338, P82976, P97503, P98168, P98169, Q05917, Q07120, Q13351, Q14549, Q14V87, Q15270, Q19A40, Q2QGD7, Q3SY56, Q3U133, Q58DK7, Q5DWN0, Q6IQX8, Q6NUN9, Q8C8V1, Q8NCA9, Q8TD94, Q8WUU4, Q924A2, Q92618, Q96RK0, Q99684, Q9BV97, Q9BYN7

Diamond homologs: A0JMA6, G5ED14, G5ED66, G5EDS1, O18381, O43316, O57682, O57685, O73917, O88436, P06601, P09082, P09083, P09084, P15863, P23757, P23758, P23759, P23760, P24610, P26367, P26630, P32114, P32115, P47236, P47238, P47239, P47240, P47242, P51974, P55166, P55771, P55864, P63015, P63016, Q00288, Q02548, Q02650, Q02962, Q06710

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PAX1	“up-regulates activity”	MEOX1	binding
PAX1	“up-regulates activity”	MEOX2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

519 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	8
Uncertain significance	249
Likely benign	216
Benign	14

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1171017	NM_001257096.2(PAX1):c.463_465del (p.Asn155del)	Pathogenic
1171018	NM_001257096.2(PAX1):c.439G>C (p.Val147Leu)	Pathogenic
1355743	NM_001257096.2(PAX1):c.112C>T (p.Gln38Ter)	Pathogenic
1451400	NM_001257096.2(PAX1):c.154_160dup (p.Gly54fs)	Pathogenic
1460324	NM_001257096.2(PAX1):c.47G>A (p.Trp16Ter)	Pathogenic
2000543	NM_001257096.2(PAX1):c.225del (p.Ser77fs)	Pathogenic
2144827	NM_001257096.2(PAX1):c.136_149dup (p.Arg51fs)	Pathogenic
2805524	NM_001257096.2(PAX1):c.24del (p.Ser9fs)	Pathogenic
3004531	NM_001257096.2(PAX1):c.201_202del (p.Gln68fs)	Pathogenic
3724536	NM_001257096.2(PAX1):c.813del (p.Val273fs)	Pathogenic
4708762	NM_001257096.2(PAX1):c.135_148dup (p.Ser50fs)	Pathogenic
4773465	NM_001257096.2(PAX1):c.256_257del (p.Ala86fs)	Pathogenic
800553	NM_001257096.2(PAX1):c.1104C>A (p.Cys368Ter)	Pathogenic
89026	NM_001257096.2(PAX1):c.497G>T (p.Gly166Val)	Pathogenic
1309932	NM_001257096.2(PAX1):c.1109_1113delinsCCAACCA (p.Tyr370fs)	Likely pathogenic
1342295	NM_001257096.2(PAX1):c.1154_1157dup (p.Tyr386Ter)	Likely pathogenic
3357711	NM_001257096.2(PAX1):c.501dup (p.Ser168fs)	Likely pathogenic
3662419	NM_001257096.2(PAX1):c.287-201_854del	Likely pathogenic
4526451	NM_001257096.2(PAX1):c.1218del (p.Gly407fs)	Likely pathogenic
4526646	NM_001257096.2(PAX1):c.703G>T (p.Glu235Ter)	Likely pathogenic
4720080	NM_001257096.2(PAX1):c.1059+2T>C	Likely pathogenic
522604	NM_001257096.2(PAX1):c.1169_1173dup (p.Pro392fs)	Likely pathogenic

SpliceAI

526 predictions. Top by Δscore:

Variant	Effect	Δscore
20:21706409:C:A	acceptor_gain	1.0000
20:21708552:CTGCA:C	acceptor_loss	1.0000
20:21708553:TGCAG:T	acceptor_loss	1.0000
20:21708554:GCA:G	acceptor_loss	1.0000
20:21708555:CA:C	acceptor_loss	1.0000
20:21708556:A:AG	acceptor_gain	1.0000
20:21708556:A:G	acceptor_loss	1.0000
20:21708556:AG:A	acceptor_gain	1.0000
20:21708556:AGG:A	acceptor_gain	1.0000
20:21708557:G:GG	acceptor_gain	1.0000
20:21708557:GG:G	acceptor_gain	1.0000
20:21708557:GGG:G	acceptor_gain	1.0000
20:21708700:GG:G	donor_loss	1.0000
20:21708702:T:A	donor_loss	1.0000
20:21709216:CCACA:C	acceptor_loss	1.0000
20:21709217:CACA:C	acceptor_loss	1.0000
20:21709218:ACAG:A	acceptor_loss	1.0000
20:21709219:C:G	acceptor_gain	1.0000
20:21709219:CAGT:C	acceptor_loss	1.0000
20:21709220:A:AC	acceptor_loss	1.0000
20:21709220:A:AG	acceptor_gain	1.0000
20:21709220:AGTC:A	acceptor_gain	1.0000
20:21709220:AGTCG:A	acceptor_gain	1.0000
20:21709221:G:GT	acceptor_gain	1.0000
20:21709221:GT:G	acceptor_gain	1.0000
20:21709221:GTC:G	acceptor_gain	1.0000
20:21709221:GTCG:G	acceptor_gain	1.0000
20:21709221:GTCGG:G	acceptor_gain	1.0000
20:21709441:GAAG:G	donor_gain	1.0000
20:21709442:AAGG:A	donor_loss	1.0000

AlphaMissense

2905 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:21706476:T:C	F109L	1.000
20:21706477:T:G	F109C	1.000
20:21706478:C:A	F109L	1.000
20:21706478:C:G	F109L	1.000
20:21706486:G:A	G112D	1.000
20:21706486:G:T	G112V	1.000
20:21706495:T:A	L115Q	1.000
20:21706519:T:A	I123N	1.000
20:21706519:T:G	I123S	1.000
20:21706528:T:C	L126P	1.000
20:21706537:T:C	L129P	1.000
20:21706540:G:T	G130V	1.000
20:21706551:T:C	C134R	1.000
20:21706552:G:A	C134Y	1.000
20:21706558:T:A	I136N	1.000
20:21706558:T:G	I136S	1.000
20:21706560:A:C	S137R	1.000
20:21706561:G:A	S137N	1.000
20:21706561:G:T	S137I	1.000
20:21706562:T:A	S137R	1.000
20:21706562:T:G	S137R	1.000
20:21706570:T:C	L140P	1.000
20:21706579:C:T	S143F	1.000
20:21706581:C:G	H144D	1.000
20:21706583:C:A	H144Q	1.000
20:21706583:C:G	H144Q	1.000
20:21706584:G:C	G145R	1.000
20:21706584:G:T	G145C	1.000
20:21706585:G:A	G145D	1.000
20:21706585:G:T	G145V	1.000

dbSNP variants (sampled 300 via entrez): RS1000010814 (20:21707286 G>C), RS1000043467 (20:21707555 C>A), RS1000287831 (20:21713260 G>A,T), RS1001055387 (20:21704794 G>A), RS1001227998 (20:21709133 A>G), RS1001285928 (20:21710444 G>A,C,T), RS1001398594 (20:21703678 A>G), RS1001773543 (20:21715023 C>T), RS1001995903 (20:21713726 C>T), RS1002110753 (20:21713973 C>T), RS1002211441 (20:21711865 T>C), RS1002353389 (20:21705988 G>A,C,T), RS1002383169 (20:21706191 G>A,C), RS1002606602 (20:21711572 C>T), RS1003051306 (20:21709507 G>A,C)

Disease associations

OMIM: gene MIM:167411 | disease phenotypes: MIM:615560, MIM:164210

GenCC curated gene-disease

Disease	Classification	Inheritance
otofaciocervical syndrome 2	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
otofaciocervical syndrome 2	Definitive	AR

Mondo (2): otofaciocervical syndrome 2 (MONDO:0014254), craniofacial microsomia (MONDO:0015397)

Orphanet (3): Oculo-auriculo-vertebral spectrum (Orphanet:141132), Otomandibular syndrome (Orphanet:141136), Goldenhar syndrome (Orphanet:374)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000107	Renal cyst
HP:0000218	High palate
HP:0000265	Mastoiditis
HP:0000293	Full cheeks
HP:0000308	Microretrognathia
HP:0000324	Facial asymmetry
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000400	Macrotia
HP:0000405	Conductive hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000411	Protruding ear
HP:0000413	Atresia of the external auditory canal
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000509	Conjunctivitis
HP:0000522	Alacrima
HP:0000592	Blue sclerae
HP:0000670	Carious teeth
HP:0000689	Dental malocclusion
HP:0000889	Abnormal clavicle morphology
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001347	Hyperreflexia
HP:0002167	Abnormal speech pattern
HP:0002342	Moderate intellectual disability
HP:0002750	Delayed skeletal maturation

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000250_2	Male-pattern baldness	1.000000e-14
GCST000251_1	Male-pattern baldness	3.000000e-15
GCST001548_7	Male-pattern baldness	2.000000e-39
GCST002819_1	Adolescent idiopathic scoliosis	3.000000e-08
GCST003637_4	facial morphology traits (multivariate analysis)	2.000000e-08
GCST003983_2	Male-pattern baldness	3.000000e-81
GCST003996_23	Monobrow	4.000000e-09
GCST004288_1	Adolescent idiopathic scoliosis	2.000000e-15
GCST004781_2	Sulfasalazine-induced agranulocytosis	4.000000e-08
GCST005116_53	Male-pattern baldness	5.000000e-45
GCST005116_54	Male-pattern baldness	6.000000e-59
GCST005116_55	Male-pattern baldness	1.000000e-105
GCST006661_179	Male-pattern baldness	7.000000e-11
GCST006902_3	Adolescent idiopathic scoliosis	2.000000e-11
GCST007015_8	Lumbar spine bone mineral density (integral)	2.000000e-07
GCST007576_266	Chronotype	3.000000e-09
GCST008789_19	Adolescent idiopathic scoliosis	1.000000e-11
GCST008839_201	Height	6.000000e-11
GCST009391_1425	Metabolite levels	8.000000e-06
GCST009464_6	Facial morphology	2.000000e-09
GCST009464_7	Facial morphology	2.000000e-11
GCST010242_172	HDL cholesterol levels	2.000000e-11
GCST010396_132	Gut microbiota (bacterial taxa, hurdle binary method)	2.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0007620	volumetric bone mineral density
EFO:0008328	chronotype measurement
EFO:0010452	adenosine diphosphate measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006053	Goldenhar Syndrome	C05.116.099.370.231.576.410; C05.660.207.231.576.410; C16.131.621.207.231.576.410

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
propionaldehyde	increases expression	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Aldehydes	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Calcitriol	decreases expression, affects cotreatment	1
Endosulfan	decreases expression	1
Malathion	increases expression	1
Nickel	increases expression	1
Phthalic Acids	increases methylation	1
Testosterone	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

10 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01674439	PHASE2	COMPLETED	Clinical Trial of Fat Grafts Supplemented With Adipose-derived Regenerative Cells
NCT05610878	PHASE1	RECRUITING	Efficacy of Preconditioned Adipose-Derived Stem Cells in Fat Grafting
NCT02224677	Not specified	COMPLETED	Craniofacial Microsomia: Longitudinal Outcomes in Children Pre-Kindergarten (CLOCK)
NCT02494752	Not specified	UNKNOWN	Role of Mesenchymal Stem Cells in Fat Grafting
NCT03806361	Not specified	COMPLETED	Fat Grafts With Adipose-derived Regenerative Cells for Soft Tissue Reconstruction in Children
NCT03861650	Not specified	COMPLETED	Evaluation of Effect of Bone Marrow Aspirate Concentrate on Distracted Mandibular Bone Properties
NCT03869021	Not specified	COMPLETED	Computer Guided for Mandibular Distraction Osteogenesis
NCT04056858	Not specified	COMPLETED	Study of a Candidate Gene Involved in Goldenhar Syndrome.
NCT04351893	Not specified	COMPLETED	Craniofacial Microsomia: Accelerating Understanding of the Significance and Etiology
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.