Is PHOX2B p.Pro290fs (c.866dup) pathogenic?

PHOX2B p.Pro290fs (c.866dup) is classified Pathogenic in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-10-23). No gnomAD frequency available for this variant; Associated with central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease.

How common is PHOX2B p.Pro290fs (c.866dup) in the general population?

PHOX2B p.Pro290fs (c.866dup) is no gnomAD frequency available for this variant (gnomAD).

How is Congenital central hypoventilation syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

PHOX2B p.Pro290fs

Q: What condition is associated with PHOX2B p.Pro290fs (c.866dup)?

PHOX2B p.Pro290fs (c.866dup) is associated with central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, neuroblastoma, susceptibility to, 2 (ClinVar).

c.866dup · rs1733868277 · VCV987239

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.31	GERP -3.2, phastCons 0.017

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHOX2B
Protein: p.Pro290fs
Coding: c.866dup
MANE Select: NM_003924
dbSNP: rs1733868277
Type: Duplication
Location: chr4:41745885 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB

Full PHOX2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuroblastoma, susceptibility to, 2

For Congenital central hypoventilation syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (France)

Similar variants

PHOX2B p.Pro290= Likely benign ★★ same residue
PHOX2B p.Ala266_Gly267insAlaAlaAlaAlaAlaAlaAlaGlyGlyLeuAlaAlaAla Likely pathogenic ★ same condition
PHOX2B p.Phe117fs Likely pathogenic ★ same condition
PHOX2B c.242-5_242-2dup Conflicting classifications of pathogenicity ★ ⚠ same condition
PHOX2B p.Pro290Ala Uncertain significance ★ ⚠ same residue
PHOX2B c.241+1G>A Likely pathogenic ★★ same condition
PHOX2B p.Gly234fs Pathogenic ★★ same condition
PHOX2B p.276GP[3] Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/phox2b-p-pro290fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown