Is PHOX2B p.Ser171Phe (c.512C>T) pathogenic?

PHOX2B p.Ser171Phe (c.512C>T) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-25). AlphaMissense: likely benign (0.1949); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Ser171Phe (c.512C>T)?

PHOX2B p.Ser171Phe (c.512C>T) is associated with hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

How common is PHOX2B p.Ser171Phe (c.512C>T) in the general population?

PHOX2B p.Ser171Phe (c.512C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHOX2B p.Ser171Phe (c.512C>T)?

AlphaMissense predicts likely benign (score 0.1949) — an in-silico prediction, not a clinical call.

PHOX2B p.Ser171Phe

c.512C>T · rs1733896388 · VCV2831033

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1949 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1949	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -11.55	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 65 bp · p 0.8 · regional, not allelic
Overall
CADD	25.4	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.Ser171Phe
Coding: c.512C>T
MANE Select: NM_003924
dbSNP: rs1733896388
Type: single nucleotide variant
Location: chr4:41746240 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.94 · 5 PDB
Residue 171: the 'disordered' region

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 p.Ser171= Likely benign ★★ same residue
PHOX2B p.Ser171Cys Uncertain significance ★ ⚠ same residue
PHOX2B p.Ser171Pro 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

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-ser171phe (accessed [today's date]).

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