Is PPP3CA p.Phe115= (c.345C>T) pathogenic?

PPP3CA p.Phe115= (c.345C>T) is classified Conflicting classifications of pathogenicity in PPP3CA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-11). Ultra-rare (popmax 0.012%, afr); Associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development.

How common is PPP3CA p.Phe115= (c.345C>T) in the general population?

PPP3CA p.Phe115= (c.345C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

PPP3CA p.Phe115=

Q: What condition is associated with PPP3CA p.Phe115= (c.345C>T)?

PPP3CA p.Phe115= (c.345C>T) is associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, developmental and epileptic encephalopathy 91 (ClinVar).

c.345C>T · rs765912235 · VCV1562032

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.77, phastCons 1
Overall
CADD	10.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,872 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000744% 12/1,613,608 alleles · ultra-rare exomes 4/1,461,526 · genomes 8/152,082 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,319
Remaining individualsnot grpmax-eligible	0.0032%	31,234
Admixed American	0.00167%	59,998

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.Phe115=
Coding: c.345C>T
MANE Select: NM_000944
dbSNP: rs765912235
Type: single nucleotide variant
Location: chr4:101108993 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 115: the 'catalytic' region; a β-strand

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.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
PPP3CA p.Arg28Trp 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-phe115 (accessed [today's date]).

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