Is PPM1D p.Ser89Arg (c.267C>G) pathogenic?

PPM1D p.Ser89Arg (c.267C>G) is classified Uncertain significance in PPM1D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-20). AlphaMissense: likely benign (0.1402); Very rare (popmax 0.0037%, amr); Associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold.

How common is PPM1D p.Ser89Arg (c.267C>G) in the general population?

PPM1D p.Ser89Arg (c.267C>G) is very rare (popmax 0.0037%, amr) (gnomAD).

How is Jansen-de Vries syndrome inherited?

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

What do computational predictors say about PPM1D p.Ser89Arg (c.267C>G)?

AlphaMissense predicts likely benign (score 0.1402) — an in-silico prediction, not a clinical call.

PPM1D p.Ser89Arg

Q: What condition is associated with PPM1D p.Ser89Arg (c.267C>G)?

PPM1D p.Ser89Arg (c.267C>G) is associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (ClinVar).

c.267C>G · rs900654745 · VCV1341773

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1402 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0037%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with gastrointestinal difficulties and high pain threshold

Computational evidence

Protein change
AlphaMissense	0.1402	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.059	GERP -0.52, phastCons 0.69
Regional constraint	o/e 0.88	unconstrained · MANE · 307 bp · p 0.13 · regional, not allelic
Overall
CADD	7.121	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0037% Admixed American · 2/54,056 alleles

Filtering AF 0.000614% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00023%

Overall 0.000254% 4/1,577,878 alleles · very rare exomes 3/1,425,696 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0037%	27,028
Remaining individualsnot grpmax-eligible	0.00328%	30,531

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.Ser89Arg
Coding: c.267C>G
MANE Select: NM_003620
dbSNP: rs900654745
Type: single nucleotide variant
Location: chr17:60600681 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 89: the ppm-type phosphatase domain; the 'interaction with chek1' region; 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.Ser89= Likely benign ★ same residue
PPM1D p.Cys407Ter Pathogenic/Likely pathogenic ★★ same condition
PPM1D p.Gln404Ter Pathogenic ★★ same condition
PPM1D p.Gln462Ter Likely pathogenic ★★ same condition
PPM1D p.Ser421Ter Pathogenic/Likely pathogenic ★★ same condition
PPM1D p.Trp427Ter Pathogenic ★★ same condition
PPM1D p.Ala152= Benign/Likely benign ★★ same condition
PPM1D c.1017+10G>T Uncertain significance ★ 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-ser89arg (accessed [today's date]).

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