Is PPM1D p.Val408fs (c.1221_1222insTC) pathogenic?

PPM1D p.Val408fs (c.12211222insTC) is classified Likely pathogenic in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-22). Absent from gnomAD; Associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold.

How common is PPM1D p.Val408fs (c.1221_1222insTC) in the general population?

PPM1D p.Val408fs (c.1221_1222insTC) is absent from gnomAD (gnomAD).

How is Jansen-de Vries syndrome inherited?

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

PPM1D p.Val408fs

Q: What condition is associated with PPM1D p.Val408fs (c.1221_1222insTC)?

PPM1D p.Val408fs (c.1221_1222insTC) is associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (ClinVar).

c.1221_1222insTC · rs2143719799 · VCV1687597

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 within the last 50 nt of the penultimate exon (5 of 6, 39 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.6	GERP -4.3

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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.Val408fs
Coding: c.1221_1222insTC
MANE Select: NM_003620
dbSNP: rs2143719799
Type: Insertion
Location: chr17:60656802 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 408: a UniProt-annotated variant site (in jdvs)

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.Pro417fs Likely pathogenic ★ same condition
PPM1D p.Gln404fs Likely pathogenic same condition
PPM1D p.Arg536fs Likely pathogenic ★★ same condition
PPM1D p.Cys407Ter Pathogenic/Likely pathogenic ★★ same condition
PPM1D p.Gln404Ter Pathogenic ★★ same condition
PPM1D p.Gln462Ter Likely pathogenic ★★ same condition
PPM1D p.Glu424fs Pathogenic/Likely pathogenic ★★ same condition
PPM1D p.Leu484fs Likely 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-val408fs (accessed [today's date]).

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