Is PHOX2B p.Ala221Pro (c.661G>C) pathogenic?

PHOX2B p.Ala221Pro (c.661G>C) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-14). AlphaMissense: likely benign (0.0858); Absent from gnomAD v4.1; Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Ala221Pro (c.661G>C)?

PHOX2B p.Ala221Pro (c.661G>C) is associated with Haddad syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PHOX2B p.Ala221Pro (c.661G>C) in the general population?

PHOX2B p.Ala221Pro (c.661G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHOX2B p.Ala221Pro (c.661G>C)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

PHOX2B p.Ala221Pro

c.661G>C · rs746684161 · VCV1051244

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Haddad syndrome

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -5.86	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 1.3	GERP -4.4, phastCons 0.47
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	11.17	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHOX2B
Protein: p.Ala221Pro
Coding: c.661G>C
MANE Select: NM_003924
dbSNP: rs746684161
Type: single nucleotide variant
Location: chr4:41746091 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 221: 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

Similar variants

PHOX2B p.Ala221Thr Uncertain significance ★★ ⚠ same residue
PHOX2B p.Ala221Ser Uncertain significance ★ ⚠ same residue
PHOX2B p.Ala221Val Conflicting classifications of pathogenicity ★ ⚠ same residue
PHOX2B p.Ala221= 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

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-ala221pro (accessed [today's date]).

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