PHOX2B

Chr 4

paired like homeobox 2B

Also known as: CCHS, NBLST2, NBPhox, PMX2B

NCBI Gene: 8929ENSG00000109132UniProt: Q99453

The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCentral hypoventilation syndrome, congenital, 1
UniProtNeuroblastoma 2

Clinical highlights

Gene-disease validity (ClinGen)
Haddad syndrome · ADDefinitivesufficient evidence for diagnostic panels2 gene-disease associations curated in total
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.
4
Active trials
82
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.34
LOEUF· LoF intol.
Multiple*
Mechanism· G2P
📖
GeneReview available — PHOX2B
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
0.34LOEUF
pLI 0.938
Z-score 2.75
OE 0.00 (0.00–0.34)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?
2.08Z-score
OE missense 0.55 (0.46–0.65)
93 obs / 169.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?
LoF OE?0.00 (0.00–0.34)
0≤0.351.4
Missense OE?0.55 (0.46–0.65)
0≤0.61.4
Synonymous OE?1.17
0≤1.21.6
LoF obs/exp: 0 / 8.8Missense obs/exp: 93 / 169.3Syn Z: -1.11

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PHOX2B · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients