PHOX2B

Chr 4AD

paired like homeobox 2B

Also known as: CCHS, NBLST2, NBPhox, PMX2B

NCBI Gene: 8929 ENSG00000109132 UniProt: Q99453 OMIM: 603851

This gene encodes a transcription factor that regulates the development of noradrenergic neurons and determines neurotransmitter phenotype in the nervous system. Mutations cause congenital central hypoventilation syndrome (often with Hirschsprung disease) and predispose to neuroblastoma, following autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.94, LOEUF 0.34), and congenital central hypoventilation syndrome typically presents in the neonatal period with life-threatening respiratory control abnormalities.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.343 OMIM phenotypes

Clinical Summary— PHOX2B

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Gene-Disease Validity (ClinGen)

Haddad syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

83 unique Pathogenic / Likely Pathogenic· 675 VUS of 1271 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PHOX2B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePHOX2B-related neuroblastoma with Hirschsprung diseaseLOFAD

definitivePHOX2B-related central hypoventilation syndrome, congenital, with or without Hirschsprung diseaseDNAD

This gene — mechanism propensity

0.4190th %ile

GOF

0.2895th %ile

LOF

0.87top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 61% of P/LP variants are LoF · LOEUF 0.34 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe propose that CCHS is partially caused by a dominant-negative effect of expanded PHOX2B due to the retention of the wild-type protein in pathogenic aggregates.1

GOFThe apparent phenotypic differences between mice carrying a loss-of-function mutation of Phox2b and CCHS patients indicates that PHOX2B mutations found in CCHS patients, all of which can produce proteins with intact DNA-binding domains, are gain-of-function mutations that alter rather than abolish p2

LOFHaploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

1271 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60

Likely Pathogenic23

VUS675

Likely Benign444

Benign23

Conflicting43

Pathogenic

Likely Pathogenic

675

VUS

444

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	36	23	1	0	60
Likely Pathogenic	15	7	1	0	23
VUS	9	620	44	2	675
Likely Benign	0	15	54	375	444
Benign	0	3	19	1	23
Conflicting	—				43
Total	60	668	119	378	1,268

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap PHOX2B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →