Is PHOX2B p.Ala260Pro (c.778G>C) pathogenic?

PHOX2B p.Ala260Pro (c.778G>C) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-09). AlphaMissense: likely benign (0.0745); Ultra-rare (popmax 0.0193%, amr); Associated with neuroblastoma, susceptibility to, 2.

What condition is associated with PHOX2B p.Ala260Pro (c.778G>C)?

PHOX2B p.Ala260Pro (c.778G>C) is associated with neuroblastoma, susceptibility to, 2, hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

How common is PHOX2B p.Ala260Pro (c.778G>C) in the general population?

PHOX2B p.Ala260Pro (c.778G>C) is ultra-rare (popmax 0.0193%, amr) (gnomAD).

What do computational predictors say about PHOX2B p.Ala260Pro (c.778G>C)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

PHOX2B p.Ala260Pro

c.778G>C · rs1383528417 · VCV2561575

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0193%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neuroblastoma, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.038, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	20.4	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 0.0193% Admixed American · 5/25,888 alleles

Filtering AF 0.00754% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00488%

Overall 0.000387% 5/1,290,860 alleles · ultra-rare exomes 0/1,142,714 · genomes 5/148,146 · joint denominator

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.Ala260Pro
Coding: c.778G>C
MANE Select: NM_003924
dbSNP: rs1383528417
Type: single nucleotide variant
Location: chr4:41745974 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 260: an α-helix; the 'disordered' region

Full PHOX2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuroblastoma, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome Haddad syndrome

Similar variants

PHOX2B p.Ala260Thr Uncertain significance ★★ ⚠ same residue
PHOX2B p.Ala260Val Uncertain significance ★★ ⚠ same residue
PHOX2B p.Ala260= Likely benign ★ same residue
PHOX2B p.Ala260del Likely benign ★★ same residue
PHOX2B p.Ala260_Gly261insAlaAlaAlaAlaAlaAlaAla Pathogenic ★ same residue
PHOX2B p.Ala260_Gly261insAlaAlaAlaAlaAlaAlaAlaAlaAla Pathogenic ★ same residue
PHOX2B p.Ala260_Gly261insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla Pathogenic ★ same residue
PHOX2B p.Ala260delinsGlyArgArgArgGlnArgGlnArgArgGlnPro Pathogenic ★ same residue

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-ala260pro (accessed [today's date]).

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