Is PHOX2B p.Ser207fs (c.618dup) pathogenic?

PHOX2B p.Ser207fs (c.618dup) is classified Pathogenic in PHOX2B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-24). Very rare (popmax 0.00135%, afr); Associated with PHOX2B-related disorder.

What condition is associated with PHOX2B p.Ser207fs (c.618dup)?

PHOX2B p.Ser207fs (c.618dup) is associated with PHOX2B-related disorder, central hypoventilation syndrome, congenital (ClinVar).

How common is PHOX2B p.Ser207fs (c.618dup) in the general population?

PHOX2B p.Ser207fs (c.618dup) is very rare (popmax 0.00135%, afr) (gnomAD).

PHOX2B p.Ser207fs

c.618dup · rs587776626 · VCV6009

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Conditions

PHOX2B-related disorder

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 4.6	GERP 0.23, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00135% African / African-American · 1/74,250 alleles

Overall 6.24e-05% 1/1,601,452 alleles · very rare exomes 1/1,449,536 · genomes 0/151,916 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PHOX2B
Protein: p.Ser207fs
Coding: c.618dup
MANE Select: NM_003924
dbSNP: rs587776626
Type: Duplication
Location: chr4:41746133 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 207: the 'disordered' region

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

Disease context

PHOX2B-related disorder

Also linked: central hypoventilation syndrome, congenital

Similar variants

PHOX2B p.Ala256_Ala260dup Pathogenic ★★ same condition
PHOX2B p.Ser207Ile Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro229fs Pathogenic ★ same condition
PHOX2B p.Ser207Gly Uncertain significance ★ ⚠ same residue
PHOX2B p.Ser207= Likely benign ★ same residue
PHOX2B p.Gly270fs Likely pathogenic same condition
PHOX2B p.Arg141Gln Pathogenic/Likely pathogenic ★★ same condition
PHOX2B p.Gln98Ter Pathogenic ★★ 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-ser207fs (accessed [today's date]).

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