Is PPP3CA p.Pro9Thr (c.25C>A) pathogenic?

PPP3CA p.Pro9Thr (c.25C>A) is classified Conflicting classifications of pathogenicity in PPP3CA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.0547); Ultra-rare (popmax 0.0447%, eas); Associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development.

How common is PPP3CA p.Pro9Thr (c.25C>A) in the general population?

PPP3CA p.Pro9Thr (c.25C>A) is ultra-rare (popmax 0.0447%, eas) (gnomAD).

What do computational predictors say about PPP3CA p.Pro9Thr (c.25C>A)?

AlphaMissense predicts likely benign (score 0.0547) — an in-silico prediction, not a clinical call.

PPP3CA p.Pro9Thr

Q: What condition is associated with PPP3CA p.Pro9Thr (c.25C>A)?

PPP3CA p.Pro9Thr (c.25C>A) is associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, developmental and epileptic encephalopathy 91 (ClinVar).

c.25C>A · rs746412506 · VCV1981080

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0547 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0447%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Computational evidence

Protein change
AlphaMissense	0.0547	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -5.26	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 151 kb · p 0.018 · regional, not allelic
Overall
CADD	24.2	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 0.0447% East Asian · 20/44,768 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.00261% 42/1,611,782 alleles · ultra-rare exomes 42/1,459,514 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0447%	2,238
European (non-Finnish)	0.00187%	53,603

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: PPP3CA
Protein: p.Pro9Thr
Coding: c.25C>A
MANE Select: NM_000944
dbSNP: rs746412506
Type: single nucleotide variant
Location: chr4:101346772 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB

Full PPP3CA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy 91

Similar variants

PPP3CA p.Pro9= Likely benign ★ same residue
PPP3CA p.Ala447Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPP3CA p.Arg254Ser Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Asp234Glu Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Glu282Lys Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.His92Arg Pathogenic/Likely pathogenic ★★ same condition
PPP3CA c.860+3G>A Uncertain significance ★★ same condition
PPP3CA p.Arg28Gln 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/ppp3ca-p-pro9thr (accessed [today's date]).

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