Is PHOX2B p.Pro269Arg (c.806C>G) pathogenic?

PHOX2B p.Pro269Arg (c.806C>G) is classified Uncertain significance in PHOX2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-09). AlphaMissense: likely benign (0.1857); Very rare (popmax 8.81e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Pro269Arg (c.806C>G)?

PHOX2B p.Pro269Arg (c.806C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PHOX2B p.Pro269Arg (c.806C>G) in the general population?

PHOX2B p.Pro269Arg (c.806C>G) is very rare (popmax 8.81e-05%, nfe) (gnomAD).

What do computational predictors say about PHOX2B p.Pro269Arg (c.806C>G)?

AlphaMissense predicts likely benign (score 0.1857) — an in-silico prediction, not a clinical call.

PHOX2B p.Pro269Arg

c.806C>G · rs1350901284 · VCV2625344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.81e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1857	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.81e-05% European (non-Finnish) · 1/1,135,192 alleles

Overall 7.28e-05% 1/1,372,752 alleles · very rare

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.Pro269Arg
Coding: c.806C>G
MANE Select: NM_003924
dbSNP: rs1350901284
Type: single nucleotide variant
Location: chr4:41745946 (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

Similar variants

PHOX2B p.Pro269Leu Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro269= Likely benign ★★ same residue
PHOX2B p.Pro269Ser Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro269_Gly270insAlaAlaAlaGlyGlyPro Uncertain significance ★★ same residue
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-pro269arg (accessed [today's date]).

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