Is PHOX2B p.Pro204Ala (c.610C>G) pathogenic?

PHOX2B p.Pro204Ala (c.610C>G) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-23). AlphaMissense: likely benign (0.0639); Very rare (popmax 0.000339%, nfe); Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Pro204Ala (c.610C>G)?

PHOX2B p.Pro204Ala (c.610C>G) is associated with Haddad syndrome, hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 2 (ClinVar).

How common is PHOX2B p.Pro204Ala (c.610C>G) in the general population?

PHOX2B p.Pro204Ala (c.610C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PHOX2B p.Pro204Ala (c.610C>G)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

PHOX2B p.Pro204Ala

c.610C>G · rs1292727082 · VCV574119

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0639 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Haddad syndrome

Computational evidence

Protein change
AlphaMissense	0.0639	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -8.16	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 7.9	GERP -1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	20.1	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 0.000339% European (non-Finnish) · 4/1,178,914 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,609,172 alleles · very rare exomes 4/1,457,034 · genomes 0/152,138 · joint denominator

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.Pro204Ala
Coding: c.610C>G
MANE Select: NM_003924
dbSNP: rs1292727082
Type: single nucleotide variant
Location: chr4:41746142 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 204: the 'disordered' region

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

Disease context

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

Also linked: hereditary neoplastic syndrome neuroblastoma, susceptibility to, 2

Similar variants

PHOX2B p.Pro204Thr Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro204= Likely benign ★★ same residue
PHOX2B p.Pro204His Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro204Leu Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro204Ser Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro204_Thr205insAsnPro Uncertain significance ★★ same residue
PHOX2B c.241+1G>A Likely pathogenic ★★ same condition
PHOX2B c.242-1G>A 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-pro204ala (accessed [today's date]).

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