Is PPM1D p.Arg536fs (c.1606del) pathogenic?

PPM1D p.Arg536fs (c.1606del) is classified Likely pathogenic in PPM1D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-21). Absent from gnomAD v4.1; Associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold.

How common is PPM1D p.Arg536fs (c.1606del) in the general population?

PPM1D p.Arg536fs (c.1606del) is absent from gnomAD v4.1 (gnomAD).

How is Jansen-de Vries syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PPM1D p.Arg536fs

Q: What condition is associated with PPM1D p.Arg536fs (c.1606del)?

PPM1D p.Arg536fs (c.1606del) is associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (ClinVar).

c.1606del · rs2031564242 · VCV976152

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,136)

Conditions

intellectual developmental disorder with gastrointestinal difficulties and high pain threshold

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 1.2	GERP -1.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,614,136). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PPM1D
Protein: p.Arg536fs
Coding: c.1606del
MANE Select: NM_003620
dbSNP: rs2031564242
Type: Deletion
Location: chr17:60663337 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 536: 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

Disease context

intellectual developmental disorder with gastrointestinal difficulties and high pain threshold — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Jansen-de Vries syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy

Similar variants

PPM1D p.Pro413fs Likely pathogenic ★★ same condition
PPM1D p.Tyr401fs Pathogenic/Likely pathogenic ★★ same condition
PPM1D p.Arg429_Val430insTer Pathogenic ★ same condition
PPM1D p.Asn431_Ser432insTer Likely pathogenic ★ same condition
PPM1D p.Ile486fs Pathogenic ★ same condition
PPM1D p.Pro471fs Likely pathogenic ★ same condition
PPM1D p.Pro518fs Likely pathogenic ★ same condition
PPM1D p.Ser503fs Pathogenic ★ 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/ppm1d-p-arg536fs (accessed [today's date]).

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