Is PPM1D p.Ser44Trp (c.131C>G) pathogenic?

PPM1D p.Ser44Trp (c.131C>G) is classified Conflicting classifications of pathogenicity in PPM1D (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.1438); Ultra-rare (popmax 0.0483%, nfe); Associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold.

How common is PPM1D p.Ser44Trp (c.131C>G) in the general population?

PPM1D p.Ser44Trp (c.131C>G) is ultra-rare (popmax 0.0483%, nfe) (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.Ser44Trp (c.131C>G)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

PPM1D p.Ser44Trp

Q: What condition is associated with PPM1D p.Ser44Trp (c.131C>G)?

PPM1D p.Ser44Trp (c.131C>G) is associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (ClinVar).

c.131C>G · rs373862041 · VCV1049549

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with gastrointestinal difficulties and high pain threshold

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 307 bp · p 0.13 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0483% European (non-Finnish) · 555/1,149,112 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0436%

Overall 0.0399% 620/1,553,936 alleles · ultra-rare exomes 567/1,401,658 · genomes 53/152,278 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0676%	1,479
European (non-Finnish)grpmax	0.0483%	2,070
Remaining individualsnot grpmax-eligible	0.0316%	3,169
Ashkenazi Jewishnot grpmax-eligible	0.00699%	14,313
African / African-American	0.00545%	18,339

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser44Trp
Coding: c.131C>G
MANE Select: NM_003620
dbSNP: rs373862041
Type: single nucleotide variant
Location: chr17:60600545 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 44: 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.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.Ser89Arg Uncertain significance ★★ ⚠ 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-ser44trp (accessed [today's date]).

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