Is PHOX2B p.Pro46Gln (c.137C>A) pathogenic?

PHOX2B p.Pro46Gln (c.137C>A) is classified Uncertain significance in PHOX2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.8479); Very rare (popmax 0.00195%, nfe); Associated with Haddad syndrome.

What condition is associated with PHOX2B p.Pro46Gln (c.137C>A)?

PHOX2B p.Pro46Gln (c.137C>A) is associated with Haddad syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PHOX2B p.Pro46Gln (c.137C>A) in the general population?

PHOX2B p.Pro46Gln (c.137C>A) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about PHOX2B p.Pro46Gln (c.137C>A)?

AlphaMissense predicts likely pathogenic (score 0.8479) — an in-silico prediction, not a clinical call.

PHOX2B p.Pro46Gln

c.137C>A · rs1381435898 · VCV819044

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Haddad syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.8479	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 1,190 bp · p 2e-05 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00195% European (non-Finnish) · 23/1,180,020 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,614,038 alleles · very rare exomes 22/1,461,870 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,305
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Pro46Gln
Coding: c.137C>A
MANE Select: NM_003924
dbSNP: rs1381435898
Type: single nucleotide variant
Location: chr4:41748474 (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-pro46gln (accessed [today's date]).

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