Is PHOX2B p.Ser66fs (c.196del) pathogenic?

PHOX2B p.Ser66fs (c.196del) is classified Pathogenic in PHOX2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Ser66fs (c.196del)?

PHOX2B p.Ser66fs (c.196del) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PHOX2B p.Ser66fs (c.196del) in the general population?

PHOX2B p.Ser66fs (c.196del) is no gnomAD frequency available for this variant (gnomAD).

PHOX2B p.Ser66fs

c.196del · rs2552097167 · VCV3223580

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHOX2B
Protein: p.Ser66fs
Coding: c.196del
MANE Select: NM_003924
dbSNP: rs2552097167
Type: Deletion
Location: chr4:41748415 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB

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

Similar variants

PHOX2B p.Gln271fs Uncertain significance ★★ same condition
PHOX2B p.Gly217_Ala223del Uncertain significance ★★ same condition
PHOX2B p.Ala226fs Pathogenic ★ same condition
PHOX2B p.Asp193fs Pathogenic ★ same condition
PHOX2B p.Leu131fs Pathogenic ★ same condition
PHOX2B p.Pro218fs Pathogenic ★ same condition
PHOX2B p.Pro279fs Pathogenic ★ same condition
PHOX2B p.Ser311fs Pathogenic ★ 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-ser66fs (accessed [today's date]).

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