Is PHOX2B p.Ala254= (c.762A>G) pathogenic?

PHOX2B p.Ala254= (c.762A>G) is classified Likely benign in PHOX2B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-25). Very rare (popmax 0.00159%, afr); Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Ala254= (c.762A>G)?

PHOX2B p.Ala254= (c.762A>G) is associated with Haddad syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PHOX2B p.Ala254= (c.762A>G) in the general population?

PHOX2B p.Ala254= (c.762A>G) is very rare (popmax 0.00159%, afr) (gnomAD).

PHOX2B p.Ala254=

c.762A>G · rs17884724 · VCV695516

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00159%, afr)

Conditions

Haddad syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.4
Overall
CADD	0.887	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00159% African / African-American · 1/62,790 alleles

Filtering AF 3.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.3e-05%

Overall 0.000243% 3/1,235,968 alleles · very rare exomes 3/1,089,222 · genomes 0/146,746 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00159%	62,790
European (non-Finnish)	0.000202%	495,187

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.Ala254=
Coding: c.762A>G
MANE Select: NM_003924
dbSNP: rs17884724
Type: single nucleotide variant
Location: chr4:41745990 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 254: a UniProt-annotated variant site (sequence variant); 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

Also linked: hereditary neoplastic syndrome

Similar variants

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
PHOX2B c.241+5G>A Uncertain significance ★★ same condition
PHOX2B c.241+6G>T Uncertain significance ★★ same condition
PHOX2B c.429+4C>A 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-ala254 (accessed [today's date]).

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