Is PPM1D p.Ser575Phe (c.1724C>T) pathogenic?

PPM1D p.Ser575Phe (c.1724C>T) is classified Uncertain significance in PPM1D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: likely benign (0.186); Very rare (popmax 0.000508%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PPM1D p.Ser575Phe (c.1724C>T)?

PPM1D p.Ser575Phe (c.1724C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PPM1D p.Ser575Phe (c.1724C>T) in the general population?

PPM1D p.Ser575Phe (c.1724C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about PPM1D p.Ser575Phe (c.1724C>T)?

AlphaMissense predicts likely benign (score 0.186) — an in-silico prediction, not a clinical call.

PPM1D p.Ser575Phe

c.1724C>T · rs1000741337 · VCV2485671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.186	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -7.88	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 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,837 bp · p 0.58 · regional, not allelic
Overall
CADD	26.5	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 0.000508% European (non-Finnish) · 6/1,180,032 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,854 alleles · very rare

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.Ser575Phe
Coding: c.1724C>T
MANE Select: NM_003620
dbSNP: rs1000741337
Type: single nucleotide variant
Location: chr17:60663458 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 575: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPM1D p.Gln404Ter Pathogenic ★★ same condition
PPM1D p.Arg357Cys Uncertain significance ★★ ⚠ same condition
PPM1D p.Arg582Cys Uncertain significance ★★ same condition
PPM1D p.Cys605Tyr Uncertain significance ★★ ⚠ same condition
PPM1D p.Gly60Asp Uncertain significance ★★ ⚠ same condition
PPM1D p.Ile371Met Uncertain significance ★★ ⚠ same condition
PPM1D p.Leu58Phe Uncertain significance ★★ ⚠ same condition
PPM1D p.Lys522Arg 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-ser575phe (accessed [today's date]).

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