Is PHOX2B p.Ala249Val (c.746C>T) pathogenic?

PHOX2B p.Ala249Val (c.746C>T) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.2306); Very rare (popmax 0.0051%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Ala249Val (c.746C>T)?

PHOX2B p.Ala249Val (c.746C>T) is associated with hereditary neoplastic syndrome, Haddad syndrome, neuroblastoma, susceptibility to, 2 (ClinVar).

How common is PHOX2B p.Ala249Val (c.746C>T) in the general population?

PHOX2B p.Ala249Val (c.746C>T) is very rare (popmax 0.0051%, nfe) (gnomAD).

What do computational predictors say about PHOX2B p.Ala249Val (c.746C>T)?

AlphaMissense predicts likely benign (score 0.2306) — an in-silico prediction, not a clinical call.

PHOX2B p.Ala249Val

c.746C>T · rs752867315 · VCV952953

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0051%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2306	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -9.36	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 5	GERP -2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 340 bp · p 0.36 · regional, not allelic
Overall
CADD	15.85	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

Grpmax group 0.0051% European (non-Finnish) · 47/922,034 alleles

Filtering AF 0.00393% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00352%

Overall 0.00434% 49/1,128,256 alleles · very rare exomes 45/982,686 · genomes 4/145,570 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0051%	19,618
African / African-American	0.00335%	29,875

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.Ala249Val
Coding: c.746C>T
MANE Select: NM_003924
dbSNP: rs752867315
Type: single nucleotide variant
Location: chr4:41746006 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 249: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Haddad syndrome neuroblastoma, susceptibility to, 2

Similar variants

PHOX2B p.Ala249Thr 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.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

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-ala249val (accessed [today's date]).

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