Is PPM1D p.Cys603Tyr (c.1808G>A) pathogenic?

PPM1D p.Cys603Tyr (c.1808G>A) is classified Uncertain significance in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-08). AlphaMissense: likely pathogenic (0.9637); Very rare (popmax 0.00267%, afr).

How common is PPM1D p.Cys603Tyr (c.1808G>A) in the general population?

PPM1D p.Cys603Tyr (c.1808G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PPM1D p.Cys603Tyr (c.1808G>A)?

AlphaMissense predicts likely pathogenic (score 0.9637) — an in-silico prediction, not a clinical call.

PPM1D p.Cys603Tyr

c.1808G>A · rs1421958284 · VCV2884721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9637	likely pathogenic
REVEL	0.451	indeterminate
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,837 bp · p 0.58 · regional, not allelic
Overall
CADD	25.7	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 0.00267% African / African-American · 2/74,882 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000249% 4/1,606,006 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,441
East Asian	0.00223%	44,850
European (non-Finnish)	8.49e-05%	1,178,375

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.Cys603Tyr
Coding: c.1808G>A
MANE Select: NM_003620
dbSNP: rs1421958284
Type: single nucleotide variant
Location: chr17:60663542 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 603: 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)

Full PPM1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPM1D p.Cys603fs Uncertain significance ★ same residue
PPM1D p.Cys407Ter Pathogenic/Likely pathogenic ★★ same type
PPM1D p.Gln404Ter Pathogenic ★★ same type
PPM1D p.Gln462Ter Likely pathogenic ★★ same type
PPM1D p.Glu423Ter Pathogenic ★★ same type
PPM1D p.Ser421Ter Pathogenic/Likely pathogenic ★★ same type
PPM1D p.Trp427Ter Pathogenic ★★ same type
PPM1D p.Arg357Cys Uncertain significance ★★ ⚠ same type

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-cys603tyr (accessed [today's date]).

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