PHOX2A

Chr 11AR

paired like homeobox 2A

Also known as: ARIX, CFEOM2, FEOM2, NCAM2, PMX2A

NCBI Gene: 401ENSG00000165462UniProt: O14813

The protein encoded by this gene contains a paired-like homeodomain most similar to that of the Drosophila aristaless gene product. The encoded protein plays a central role in development of the autonomic nervous system. It regulates the expression of tyrosine hydroxylase and dopamine beta-hydroxylase, two catecholaminergic biosynthetic enzymes essential for the differentiation and maintenance of the noradrenergic neurotransmitter phenotype. The encoded protein has also been shown to regulate transcription of the alpha3 nicotinic acetylcholine receptor gene. Mutations in this gene have been associated with autosomal recessive congenital fibrosis of the extraocular muscles. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Fibrosis of extraocular muscles, congenital, 2MIM #602078
AR
54
ClinVar variants
11
Pathogenic / LP
0.49
pLI score
0
Active trials
Clinical Summary— PHOX2A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.17) despite low pLI — interpret in context.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 35 VUS of 54 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.80LOEUF
pLI 0.490
Z-score 1.88
OE 0.17 (0.06–0.80)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.60Z-score
OE missense 0.57 (0.47–0.70)
63 obs / 110.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.06–0.80)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.47–0.70)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.59
0≤1.21.6
LoF obs/exp: 1 / 6.0Missense obs/exp: 63 / 110.3Syn Z: 2.29

ClinVar Variant Classifications

54 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
VUS35
Likely Benign5
Benign3
11
Pathogenic
35
VUS
5
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
9
0
11
Likely Pathogenic
0
0
0
0
0
VUS
0
31
4
0
35
Likely Benign
0
0
1
4
5
Benign
0
0
2
1
3
Total23116554

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PHOX2A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PHOX2A-related fibrosis of extraocular muscles, congenital

strong
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Fibrosis of extraocular muscles, congenital, 2

MIM #602078

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PHOX2A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.
Lee AS et al.·Nat Commun
2024
The genetic basis of complex strabismus.
Engle EC·Pediatr Res
2006Review
Congenital fibrosis of the extraocular muscles.
Heidary G et al.·Semin Ophthalmol
2008Review
PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma.
Longo L et al.·Int J Oncol
2008
Transcriptional regulation of TLX2 and impaired intestinal innervation: possible role of the PHOX2A and PHOX2B genes.
Borghini S et al.·Eur J Hum Genet
2007
Axons get ahead: Insights into axon guidance and congenital cranial dysinnervation disorders.
Chilton JK et al.·Dev Neurobiol
2017Review
Paired-like homeodomain proteins, Phox2a and Phox2b, are responsible for noradrenergic cell-specific transcription of the dopamine beta-hydroxylase gene.
Yang C et al.·J Neurochem
1998
A novel PHOX2A/ARIX mutation in an Iranian family with congenital fibrosis of extraocular muscles type 2 (CFEOM2).
Yazdani A et al.·Am J Ophthalmol
2003
Transcription factor PHOX2A regulates the human alpha3 nicotinic receptor subunit gene promoter.
Benfante R et al.·J Biol Chem
2007
Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription.
Adachi M et al.·DNA Cell Biol
2000
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools