Is PHOX2B p.Ala241Pro (c.721G>C) pathogenic?

PHOX2B p.Ala241Pro (c.721G>C) is classified Uncertain significance in PHOX2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-17). AlphaMissense: likely benign (0.0708); Absent from gnomAD v4.1; Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Ala241Pro (c.721G>C)?

PHOX2B p.Ala241Pro (c.721G>C) is associated with Haddad syndrome (ClinVar).

How common is PHOX2B p.Ala241Pro (c.721G>C) in the general population?

PHOX2B p.Ala241Pro (c.721G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHOX2B p.Ala241Pro (c.721G>C)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

PHOX2B p.Ala241Pro

c.721G>C · rs2552096828 · VCV2761047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,206,854)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Haddad syndrome

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.47, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	17.2	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

No allele count reported in gnomAD v4.1 (AN 1,206,854). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHOX2B
Protein: p.Ala241Pro
Coding: c.721G>C
MANE Select: NM_003924
dbSNP: rs2552096828
Type: single nucleotide variant
Location: chr4:41746031 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 241: a UniProt-annotated variant site (in cchs1); the 'disordered' region; an α-helix

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

Similar variants

PHOX2B p.Ala241Thr Uncertain significance ★ ⚠ same residue
PHOX2B p.Ala241Glu Uncertain significance ★ ⚠ same residue
PHOX2B p.Ala241Ser Uncertain significance ★ ⚠ same residue
PHOX2B p.Ala241= 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.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-ala241pro (accessed [today's date]).

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