Is PHOX2B p.Phe33Ile (c.97T>A) pathogenic?

PHOX2B p.Phe33Ile (c.97T>A) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-31). AlphaMissense: likely pathogenic (0.8462); Absent from gnomAD v4.1; Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Phe33Ile (c.97T>A)?

PHOX2B p.Phe33Ile (c.97T>A) is associated with Haddad syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PHOX2B p.Phe33Ile (c.97T>A) in the general population?

PHOX2B p.Phe33Ile (c.97T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHOX2B p.Phe33Ile (c.97T>A)?

AlphaMissense predicts likely pathogenic (score 0.8462) — an in-silico prediction, not a clinical call.

PHOX2B p.Phe33Ile

c.97T>A · rs1043632230 · VCV2563104

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8462 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Haddad syndrome

Computational evidence

Protein change
AlphaMissense	0.8462	likely pathogenic
REVEL	0.567	indeterminate
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 1,190 bp · p 2e-05 · regional, not allelic
Overall
CADD	32.0	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.Phe33Ile
Coding: c.97T>A
MANE Select: NM_003924
dbSNP: rs1043632230
Type: single nucleotide variant
Location: chr4:41748514 (GRCh38)

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

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-phe33ile (accessed [today's date]).

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