Is PHOX2B p.Phe117= (c.351C>T) pathogenic?

PHOX2B p.Phe117= (c.351C>T) is classified Likely benign in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-11-23). Rare (popmax 0.179%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Phe117= (c.351C>T)?

PHOX2B p.Phe117= (c.351C>T) is associated with hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

How common is PHOX2B p.Phe117= (c.351C>T) in the general population?

PHOX2B p.Phe117= (c.351C>T) is rare (popmax 0.179%, afr) (gnomAD).

PHOX2B p.Phe117=

c.351C>T · rs1169134483 · VCV1130199

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.179%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.038	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -2.2, phastCons 1
Overall
CADD	10.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.179% African / African-American · 114/63,524 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.143%

Overall 0.0187% 292/1,560,804 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.179%	557
Admixed American	0.0551%	1,815
East Asian	0.0211%	4,748
Ashkenazi Jewishnot grpmax-eligible	0.0175%	5,705
Finnishnot grpmax-eligible	0.0151%	6,623
European (non-Finnish)	0.00977%	10,232
Remaining individualsnot grpmax-eligible	0.00818%	12,227
South Asian	0.00796%	12,566

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.Phe117=
Coding: c.351C>T
MANE Select: NM_003924
dbSNP: rs1169134483
Type: single nucleotide variant
Location: chr4:41747427 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 117: a DNA-binding region; 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

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-phe117 (accessed [today's date]).

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