PPM1D p.Ser421=
c.1263A>T · VCV3712462
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00272%, afr)
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 -0.066 | GERP -4.6, phastCons 0.001 |
| Overall | ||
| CADD | 2.626 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00272%
African / African-American · 2/73,456 alleles
Filtering AF
0.000452%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000169%
Overall
0.000252%
4/1,588,488 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00272% | 36,728 |
| East Asian | 0.00224% | 44,614 |
| Admixed American | 0.00188% | 53,314 |
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
- PPM1D
- Protein
- p.Ser421=
- Coding
- c.1263A>T
- MANE Select
- NM_003620
- Type
- single nucleotide variant
- Location
- chr17:60662997 (GRCh38)
- Gene constraint
- LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.15 · 1 PDB
- Residue 421
- a UniProt-annotated variant site (in jdvs)
Similar variants
- PPM1D p.Ser421Ter Pathogenic/Likely pathogenic ★★ same residue
- PPM1D p.Ser421fs Pathogenic same residue
- PPM1D p.Cys407Ter Pathogenic/Likely pathogenic ★★ same type
- PPM1D p.Gln404Ter Pathogenic ★★ same type
- PPM1D p.Gln462Ter Likely pathogenic ★★ same type
- PPM1D p.Glu423Ter Pathogenic ★★ same type
- PPM1D p.Trp427Ter Pathogenic ★★ same type
- PPM1D p.Arg357Cys Uncertain significance ★★ ⚠ 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/ppm1d-p-ser421 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown