PHOX2B p.Ile280=
c.840C>A · rs1470625532 · VCV2903093
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00222%, sas)
Conditions
2
Haddad 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 8 | GERP -0.28, phastCons 1 |
| Overall | ||
| CADD | 10.27 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00222%
South Asian · 2/90,196 alleles
Filtering AF
0.000368%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000138%
Overall
0.000187%
3/1,605,046 alleles · very rare
exomes 3/1,453,394 · genomes 0/151,652 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00222% | 45,098 |
| European (non-Finnish) | 8.5e-05% | 1,176,186 |
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.Ile280=
- Coding
- c.840C>A
- MANE Select
- NM_003924
- dbSNP
- rs1470625532
- Type
- single nucleotide variant
- Location
- chr4:41745912 (GRCh38)
- Gene constraint
- LOEUF 0.349 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 61.94 · 5 PDB
- Residue 280
- the 'disordered' region
Similar variants
- PHOX2B p.Ile280Val Uncertain significance ★★ ⚠ same residue
- PHOX2B p.Ile280Thr 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
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-ile280 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown