Is PPM1D p.Phe534fs (c.1602del) pathogenic?

PPM1D p.Phe534fs (c.1602del) is classified Uncertain significance in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-21). Very rare (popmax 0.00223%, eas).

How common is PPM1D p.Phe534fs (c.1602del) in the general population?

PPM1D p.Phe534fs (c.1602del) is very rare (popmax 0.00223%, eas) (gnomAD).

PPM1D p.Phe534fs

c.1602del · VCV4936292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.21	GERP -4.5, phastCons 0.28
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,898 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,034 alleles · very rare exomes 3/1,461,860 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,898
European (non-Finnish)	0.000254%	393,335

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.Phe534fs
Coding: c.1602del
MANE Select: NM_003620
Type: Deletion
Location: chr17:60663334 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 534: a UniProt-annotated variant site (in jdvs); a UniProt-annotated variant site (in oc; may be associated with disease susceptibility); a UniProt-annotated variant site (in bc; may be associated with disease susceptibility; gain-of-function mutation that results in increased negative regulation of p53 expression in response to ionizing radiation exposure); a UniProt-annotated variant site (in bc; may be associated with disease susceptibility); the 'disordered' region

Full PPM1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPM1D p.Phe534_Lys535delinsTer Likely pathogenic ★ same residue
PPM1D p.Arg536fs Likely pathogenic ★★ same type
PPM1D p.Pro413fs Likely pathogenic ★★ same type
PPM1D p.Tyr401fs Pathogenic/Likely pathogenic ★★ same type
PPM1D p.Arg429_Val430insTer Pathogenic ★ same type
PPM1D p.Asn431_Ser432insTer Likely pathogenic ★ same type
PPM1D p.Cys407fs Likely pathogenic ★ same type
PPM1D p.Cys478fs Likely pathogenic ★ 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-phe534fs (accessed [today's date]).

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