PHOX2B p.Ala248=
c.744G>A · rs758533453 · VCV1667193
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00498%, eas)
Conditions
2
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 -4.6 | GERP -3.7 |
| Overall | ||
| CADD | 1.266 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00498%
East Asian · 1/20,084 alleles
Filtering AF
0.000102%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 6.9e-05%
Overall
0.000535%
6/1,120,954 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.00498% | 20,084 |
| South Asian | 0.00429% | 23,298 |
| European (non-Finnish) | 0.000436% | 229,268 |
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.Ala248=
- Coding
- c.744G>A
- MANE Select
- NM_003924
- dbSNP
- rs758533453
- Type
- single nucleotide variant
- Location
- chr4:41746008 (GRCh38)
- Gene constraint
- LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 61.94 · 5 PDB
- Residue 248
- an α-helix
Similar variants
- PHOX2B p.Ala248Val 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
- PHOX2B c.241+5G>A Uncertain significance ★★ same condition
- PHOX2B c.241+6G>T 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-ala248 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown