Is PHOX2B p.Ala80Pro (c.238G>C) pathogenic?

PHOX2B p.Ala80Pro (c.238G>C) is classified Uncertain significance in PHOX2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-29). AlphaMissense: ambiguous (0.4723); Absent from gnomAD v4.1; Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Ala80Pro (c.238G>C)?

PHOX2B p.Ala80Pro (c.238G>C) is associated with Haddad syndrome (ClinVar).

How common is PHOX2B p.Ala80Pro (c.238G>C) in the general population?

PHOX2B p.Ala80Pro (c.238G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHOX2B p.Ala80Pro (c.238G>C)?

AlphaMissense predicts ambiguous (score 0.4723) — an in-silico prediction, not a clinical call.

PHOX2B p.Ala80Pro

c.238G>C · rs550472167 · VCV1718297

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4723 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Haddad syndrome

Computational evidence

Protein change
AlphaMissense	0.4723	ambiguous
REVEL	0.502	indeterminate
SaProt	LLR -7.68	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 1,190 bp · p 2e-05 · regional, not allelic
Overall
CADD	25.1	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

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.Ala80Pro
Coding: c.238G>C
MANE Select: NM_003924
dbSNP: rs550472167
Type: single nucleotide variant
Location: chr4:41748373 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB

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.Ala80Ser Uncertain significance ★★ ⚠ same residue
PHOX2B p.Ala80Thr 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.Tyr83Ter Pathogenic/Likely pathogenic ★★ same condition
PHOX2B c.241+5G>A Uncertain significance ★★ same condition
PHOX2B c.241+6G>T Uncertain significance ★★ 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-ala80pro (accessed [today's date]).

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