PAPPA2 p.Arg346=
c.1038C>T · VCV4533653
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.379%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -5.5 | GERP -3.9 |
| Overall | ||
| CADD | 0.395 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.379%
Middle Eastern · 23/6,062 alleles
Filtering AF
0.259%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.22%
Overall
0.0256%
414/1,614,182 alleles · rare
exomes 359/1,461,892 · genomes 55/152,290 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.379% | 264 |
| Ashkenazi Jewishnot grpmax-eligible | 0.375% | 267 |
| Remaining individualsnot grpmax-eligible | 0.0496% | 2,016 |
| African / African-American | 0.0266% | 3,752 |
| Admixed American | 0.0233% | 4,287 |
| European (non-Finnish) | 0.0174% | 5,756 |
| South Asian | 0.011% | 9,107 |
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
- PAPPA2
- Protein
- p.Arg346=
- Coding
- c.1038C>T
- MANE Select
- NM_020318
- Type
- single nucleotide variant
- Location
- chr1:176594642 (GRCh38)
- Gene constraint
- LOEUF 0.549 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.65 · 1 PDB
- Residue 346
- a β-strand
Similar variants
- PAPPA2 p.Glu1126Ter Pathogenic ★★ same type
- PAPPA2 p.Arg326His Uncertain significance ★★ ⚠ same type
- PAPPA2 p.Arg617His Uncertain significance ★★ ⚠ same type
- PAPPA2 p.Leu782Arg Uncertain significance ★★ ⚠ same type
- PAPPA2 p.Phe1025Leu Uncertain significance ★★ ⚠ same type
- PAPPA2 p.Pro1397Leu Uncertain significance ★★ ⚠ same type
- PAPPA2 c.3366-16A>G Benign/Likely benign ★★ same type
- PAPPA2 p.Ala1527Ser Benign/Likely benign ★★ same type
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/pappa2-p-arg346 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown