Is PHOX2B p.Pro229Ser (c.685C>T) pathogenic?

PHOX2B p.Pro229Ser (c.685C>T) is classified Uncertain significance in PHOX2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). AlphaMissense: likely benign (0.078); Very rare (popmax 0.00298%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Pro229Ser (c.685C>T)?

PHOX2B p.Pro229Ser (c.685C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PHOX2B p.Pro229Ser (c.685C>T) in the general population?

PHOX2B p.Pro229Ser (c.685C>T) is very rare (popmax 0.00298%, amr) (gnomAD).

What do computational predictors say about PHOX2B p.Pro229Ser (c.685C>T)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

PHOX2B p.Pro229Ser

c.685C>T · rs1328080249 · VCV1755827

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00298%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP -0.015, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	15.74	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 0.00298% Admixed American · 1/33,516 alleles

Overall 0.000143% 2/1,402,062 alleles · very rare exomes 2/1,253,932 · genomes 0/148,130 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00298%	33,516
South Asian	0.00163%	61,304

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.Pro229Ser
Coding: c.685C>T
MANE Select: NM_003924
dbSNP: rs1328080249
Type: single nucleotide variant
Location: chr4:41746067 (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

Similar variants

PHOX2B p.Pro229Thr Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro229= Likely benign ★★ same residue
PHOX2B p.Pro229His 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
PHOX2B c.241+5G>A 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-pro229ser (accessed [today's date]).

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