Is PHOX2B p.Ser40= (c.120T>C) pathogenic?

PHOX2B p.Ser40= (c.120T>C) is classified Likely benign in PHOX2B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-14). Ultra-rare (popmax 0.0823%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with PHOX2B p.Ser40= (c.120T>C)?

PHOX2B p.Ser40= (c.120T>C) is associated with hereditary neoplastic syndrome, Haddad syndrome (ClinVar).

How common is PHOX2B p.Ser40= (c.120T>C) in the general population?

PHOX2B p.Ser40= (c.120T>C) is ultra-rare (popmax 0.0823%, sas) (gnomAD).

PHOX2B p.Ser40=

c.120T>C · rs756519209 · VCV535787

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0823%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.5, phastCons 1
Overall
CADD	18.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0823% South Asian · 75/91,088 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0617%

Overall 0.00489% 79/1,614,076 alleles · ultra-rare exomes 76/1,461,882 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0823%	1,215
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	8.47e-05%	1,180,018

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.Ser40=
Coding: c.120T>C
MANE Select: NM_003924
dbSNP: rs756519209
Type: single nucleotide variant
Location: chr4:41748491 (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

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-ser40 (accessed [today's date]).

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