Is PPP3CA p.Arg173= (c.519C>T) pathogenic?

PPP3CA p.Arg173= (c.519C>T) is classified Likely benign in PPP3CA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-14). Very rare (popmax 0.00896%, eas); Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Arg173= (c.519C>T)?

PPP3CA p.Arg173= (c.519C>T) is associated with developmental and epileptic encephalopathy 91, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ClinVar).

How common is PPP3CA p.Arg173= (c.519C>T) in the general population?

PPP3CA p.Arg173= (c.519C>T) is very rare (popmax 0.00896%, eas) (gnomAD).

PPP3CA p.Arg173=

c.519C>T · rs752462646 · VCV1530709

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00896%, eas)

Conditions

developmental and epileptic encephalopathy 91

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 -2.2	GERP -5.6
Overall
CADD	2.724	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00896% East Asian · 4/44,636 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00181%

Overall 0.00168% 27/1,608,790 alleles · very rare exomes 25/1,456,606 · genomes 2/152,184 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00896%	11,159
Admixed American	0.00506%	19,779
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,528
Remaining individualsnot grpmax-eligible	0.00321%	31,157
European (non-Finnish)	0.00136%	73,581
South Asian	0.00111%	90,076

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.Arg173=
Coding: c.519C>T
MANE Select: NM_000944
dbSNP: rs752462646
Type: single nucleotide variant
Location: chr4:101098490 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 173: the 'catalytic' region; an α-helix

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

Disease context

developmental and epileptic encephalopathy 91 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Similar variants

PPP3CA p.Arg173Cys Likely benign ★★ ⚠ same residue
PPP3CA p.Arg173His Likely benign ★★ same residue
PPP3CA p.Arg173Leu Uncertain significance ★ ⚠ same residue
PPP3CA p.Arg173Ser Uncertain significance ★ ⚠ 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

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-arg173 (accessed [today's date]).

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