Is PHOX2B p.Ser184= (c.552C>T) pathogenic?

PHOX2B p.Ser184= (c.552C>T) is classified Benign/Likely benign in PHOX2B (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.27%, nfe); Associated with central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease.

How common is PHOX2B p.Ser184= (c.552C>T) in the general population?

PHOX2B p.Ser184= (c.552C>T) is low-frequency (popmax 1.27%, nfe) (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.Ser184=

Q: What condition is associated with PHOX2B p.Ser184= (c.552C>T)?

PHOX2B p.Ser184= (c.552C>T) is associated with central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

c.552C>T · rs17885216 · VCV227015

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.27%, nfe)

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.
REVEL	0.238	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.5, phastCons 1
Overall
CADD	9.821	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.27% European (non-Finnish) · 14,950/1,179,872 alleles

Filtering AF 1.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.24%

Overall 1.12% 18,048/1,613,744 alleles · low-frequency exomes 16,528/1,461,566 · genomes 1,520/152,178 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.08%	48
European (non-Finnish)grpmax	1.27%	79
African / African-American	1.2%	83
Remaining individualsnot grpmax-eligible	1.1%	91
Middle Eastern	0.759%	132
Admixed American	0.738%	135
Amishnot grpmax-eligible	0.549%	182
Finnishnot grpmax-eligible	0.274%	365
South Asian	0.246%	407

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser184=
Coding: c.552C>T
MANE Select: NM_003924
dbSNP: rs17885216
Type: single nucleotide variant
Location: chr4:41746200 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 184: the 'disordered' region

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: hereditary neoplastic syndrome Haddad syndrome neuroblastoma, susceptibility to, 2 central hypoventilation syndrome, congenital

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.Ser184Gly Uncertain significance ★★ ⚠ same residue
PHOX2B c.241+1G>A Likely pathogenic ★★ same condition
PHOX2B c.242-1G>A Pathogenic/Likely pathogenic ★★ same condition
PHOX2B p.Arg141Gln Pathogenic/Likely pathogenic ★★ same condition
PHOX2B p.Gln98Ter Pathogenic ★★ same condition
PHOX2B p.Tyr83Ter Pathogenic/Likely pathogenic ★★ same condition
PHOX2B c.241+5G>A Uncertain significance ★★ same condition
PHOX2B c.241+6G>T 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-ser184 (accessed [today's date]).

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