Is PHOX2A p.Pro263Ser (c.787C>T) pathogenic?

PHOX2A p.Pro263Ser (c.787C>T) is classified Uncertain significance in PHOX2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-18). AlphaMissense: likely pathogenic (0.582); Very rare (popmax 0.00194%, sas); Associated with Inborn genetic diseases.

What condition is associated with PHOX2A p.Pro263Ser (c.787C>T)?

PHOX2A p.Pro263Ser (c.787C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHOX2A p.Pro263Ser (c.787C>T) in the general population?

PHOX2A p.Pro263Ser (c.787C>T) is very rare (popmax 0.00194%, sas) (gnomAD).

What do computational predictors say about PHOX2A p.Pro263Ser (c.787C>T)?

AlphaMissense predicts likely pathogenic (score 0.582) — an in-silico prediction, not a clinical call.

PHOX2A p.Pro263Ser

c.787C>T · VCV4136065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00194%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.582	likely pathogenic
REVEL	0.447	indeterminate
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 115 bp · p 0.021 · regional, not allelic
Overall
CADD	23.8	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 0.00194% South Asian · 1/51,616 alleles

Overall 0.000147% 2/1,364,496 alleles · very rare exomes 1/1,212,310 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00194%	51,616
European (non-Finnish)	9.53e-05%	1,049,410

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: PHOX2A
Protein: p.Pro263Ser
Coding: c.787C>T
MANE Select: NM_005169
Type: single nucleotide variant
Location: chr11:72239817 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.49
Residue 263: the 'disordered' region

Full PHOX2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHOX2A p.Ala152Gly Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala158Glu Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala278Asp Uncertain significance ★ same condition
PHOX2A p.Ala278Val Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala61Asp Uncertain significance ★ ⚠ same condition
PHOX2A p.Ala68Pro Uncertain significance ★ ⚠ same condition
PHOX2A p.Arg169Cys Uncertain significance ★ ⚠ same condition
PHOX2A p.Arg63His 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/phox2a-p-pro263ser (accessed [today's date]).

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