PHOX2A

Chr 11AR

paired like homeobox 2A

Also known as: ARIX, CFEOM2, FEOM2, PMX2A

NCBI Gene: 401 ENSG00000165462 UniProt: O14813 OMIM: 602753

PHOX2A encodes a homeodomain transcription factor that regulates development of the autonomic nervous system and controls expression of catecholamine biosynthetic enzymes essential for noradrenergic neurotransmitter function. Mutations cause autosomal recessive congenital fibrosis of extraocular muscles type 2, characterized by restrictive eye movement defects present from birth. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.796), reflecting its important developmental role.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Fibrosis of extraocular muscles, congenital, 2MIM #602078

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Fibrosis of extraocular muscles, congenital; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — PHOX2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.490

Z-score 1.88

OE 0.17 (0.06–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.60Z-score

OE missense 0.57 (0.47–0.70)

63 obs / 110.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.06–0.80)

0≤0.351.4

Missense OE?0.57 (0.47–0.70)

0≤0.61.4

Synonymous OE?0.59

0≤1.21.6

LoF obs/exp: 1 / 6.0Missense obs/exp: 63 / 110.3Syn Z: 2.29

Background carrier burden — how many people carry a rare variant somewhere in PHOX2A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 340

399 rare PASS variants

Rare truncating (LoF)

1 in 4,100

57 rare PASS variants

Rare synonymous (reference)

1 in 410

229 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PHOX2A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 400	1 in 5,300
South Asian	~43k	1 in 270	1 in 770
Remaining (unassigned)	~30k	1 in 280	1 in 3,200
European (Finnish)	~27k	1 in 650	1 in 3,700
Admixed American	~22k	1 in 130	1 in 2,400
African / African American	~21k	1 in 210	≈ 1 in 6,900
East Asian	~20k	1 in 290	none seen
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,882	1 in 220	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.