Is PHOX2B p.Pro202Arg (c.605C>G) pathogenic?

PHOX2B p.Pro202Arg (c.605C>G) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-08). AlphaMissense: likely benign (0.2669); Very rare (popmax 0.0017%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Pro202Arg (c.605C>G)?

PHOX2B p.Pro202Arg (c.605C>G) is associated with hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

How common is PHOX2B p.Pro202Arg (c.605C>G) in the general population?

PHOX2B p.Pro202Arg (c.605C>G) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about PHOX2B p.Pro202Arg (c.605C>G)?

AlphaMissense predicts likely benign (score 0.2669) — an in-silico prediction, not a clinical call.

PHOX2B p.Pro202Arg

c.605C>G · rs752633393 · VCV1751314

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2669	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -11.50	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	25.4	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 0.0017% European (non-Finnish) · 20/1,179,628 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00137% 20/1,459,068 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.Pro202Arg
Coding: c.605C>G
MANE Select: NM_003924
dbSNP: rs752633393
Type: single nucleotide variant
Location: chr4:41746147 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 202: 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.Pro202Ala Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro202Leu Uncertain significance ★ ⚠ same residue
PHOX2B p.Pro202= Likely benign ★ 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
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-pro202arg (accessed [today's date]).

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