Is PHOX2B p.Pro206Arg (c.617C>G) pathogenic?

PHOX2B p.Pro206Arg (c.617C>G) is classified Conflicting classifications of pathogenicity in PHOX2B (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.2732); Ultra-rare (popmax 0.0509%, sas); Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Pro206Arg (c.617C>G)?

PHOX2B p.Pro206Arg (c.617C>G) is associated with Haddad syndrome, hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 2 (ClinVar).

How common is PHOX2B p.Pro206Arg (c.617C>G) in the general population?

PHOX2B p.Pro206Arg (c.617C>G) is ultra-rare (popmax 0.0509%, sas) (gnomAD).

What do computational predictors say about PHOX2B p.Pro206Arg (c.617C>G)?

AlphaMissense predicts likely benign (score 0.2732) — an in-silico prediction, not a clinical call.

PHOX2B p.Pro206Arg

c.617C>G · rs587778606 · VCV135034

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0509%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Haddad syndrome

Computational evidence

Protein change
AlphaMissense	0.2732	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -9.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP -0.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0509% South Asian · 46/90,300 alleles

Filtering AF 0.0392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.00374% 60/1,604,220 alleles · ultra-rare exomes 56/1,452,268 · genomes 4/151,952 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0509%	1,963
Remaining individualsnot grpmax-eligible	0.00805%	12,428
European (non-Finnish)	0.000765%	130,793

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.Pro206Arg
Coding: c.617C>G
MANE Select: NM_003924
dbSNP: rs587778606
Type: single nucleotide variant
Location: chr4:41746135 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 206: 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 central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

Similar variants

PHOX2B p.Pro206Leu Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro206Ser Uncertain significance ★★ ⚠ same residue
PHOX2B p.Pro206= Likely benign ★ same residue
PHOX2B p.Pro206_Ser207insThrPro 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-pro206arg (accessed [today's date]).

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