Is PHOX2A p.Ala68Pro (c.202G>C) pathogenic?

PHOX2A p.Ala68Pro (c.202G>C) is classified Uncertain significance in PHOX2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.1379); Ultra-rare (popmax 0.0305%, mid); Associated with Inborn genetic diseases.

What condition is associated with PHOX2A p.Ala68Pro (c.202G>C)?

PHOX2A p.Ala68Pro (c.202G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PHOX2A p.Ala68Pro (c.202G>C) in the general population?

PHOX2A p.Ala68Pro (c.202G>C) is ultra-rare (popmax 0.0305%, mid) (gnomAD).

What do computational predictors say about PHOX2A p.Ala68Pro (c.202G>C)?

AlphaMissense predicts likely benign (score 0.1379) — an in-silico prediction, not a clinical call.

PHOX2A p.Ala68Pro

c.202G>C · rs764865688 · VCV2272413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1379 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0305%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1379	likely benign
REVEL	0.384	indeterminate
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,947 bp · p 0.076 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0305% Middle Eastern · 1/3,276 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.0118% 147/1,249,040 alleles · ultra-rare exomes 130/1,096,964 · genomes 17/152,076 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0305%	3,276
European (non-Finnish)	0.0139%	7,215
Remaining individualsnot grpmax-eligible	0.0108%	9,256
Admixed American	0.00841%	11,887
Finnishnot grpmax-eligible	0.0029%	34,448

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.Ala68Pro
Coding: c.202G>C
MANE Select: NM_005169
dbSNP: rs764865688
Type: single nucleotide variant
Location: chr11:72243803 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.49

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.Ala68Thr Uncertain significance ⚠ same residue
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.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-ala68pro (accessed [today's date]).

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