Is PHOX2B p.Pro269= (c.807T>C) pathogenic?

PHOX2B p.Pro269= (c.807T>C) is classified Likely benign in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-24). Very rare (popmax 0.00212%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Pro269= (c.807T>C)?

PHOX2B p.Pro269= (c.807T>C) is associated with hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

How common is PHOX2B p.Pro269= (c.807T>C) in the general population?

PHOX2B p.Pro269= (c.807T>C) is very rare (popmax 0.00212%, nfe) (gnomAD).

PHOX2B p.Pro269=

c.807T>C · rs755371263 · VCV467749

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.5	GERP -3.6
Overall
CADD	3.895	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 24/1,134,734 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0012%

Overall 0.00164% 25/1,521,748 alleles · very rare exomes 23/1,371,370 · genomes 2/150,378 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,281
South Asian	0.00126%	79,408

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.Pro269=
Coding: c.807T>C
MANE Select: NM_003924
dbSNP: rs755371263
Type: single nucleotide variant
Location: chr4:41745945 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 269: 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.Pro269Leu Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro269Arg Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro269Ser Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro269_Gly270insAlaAlaAlaGlyGlyPro 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

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-pro269 (accessed [today's date]).

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