Is PHOX2B p.Pro229= (c.687C>A) pathogenic?

PHOX2B p.Pro229= (c.687C>A) is classified Likely benign in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-27). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Pro229= (c.687C>A)?

PHOX2B p.Pro229= (c.687C>A) is associated with hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

How common is PHOX2B p.Pro229= (c.687C>A) in the general population?

PHOX2B p.Pro229= (c.687C>A) is absent from gnomAD v4.1 (gnomAD).

PHOX2B p.Pro229=

c.687C>A · rs1391920139 · VCV1991471

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,390,704)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.178	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.3	GERP -4
Overall
CADD	2.095	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,390,704). 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.Pro229=
Coding: c.687C>A
MANE Select: NM_003924
dbSNP: rs1391920139
Type: single nucleotide variant
Location: chr4:41746065 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 229: the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Haddad syndrome

Similar variants

PHOX2B p.Pro229Thr Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro229His Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro229Ser 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

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-pro229 (accessed [today's date]).

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