Is PPP3CA p.Ser434Arg (c.1302C>A) pathogenic?

PPP3CA p.Ser434Arg (c.1302C>A) is classified Uncertain significance in PPP3CA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-24). AlphaMissense: likely pathogenic (0.8558); Very rare (popmax 0.00401%, afr); Associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development.

How common is PPP3CA p.Ser434Arg (c.1302C>A) in the general population?

PPP3CA p.Ser434Arg (c.1302C>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PPP3CA p.Ser434Arg (c.1302C>A)?

AlphaMissense predicts likely pathogenic (score 0.8558) — an in-silico prediction, not a clinical call.

PPP3CA p.Ser434Arg

Q: What condition is associated with PPP3CA p.Ser434Arg (c.1302C>A)?

PPP3CA p.Ser434Arg (c.1302C>A) is associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, developmental and epileptic encephalopathy 91 (ClinVar).

c.1302C>A · rs369318194 · VCV2821125

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8558 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Computational evidence

Protein change
AlphaMissense	0.8558	likely pathogenic
REVEL	0.273	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -5.6, phastCons 0.84
Regional constraint	o/e 0.40	unconstrained · MANE · 170 kb · p 4.9e-41 · regional, not allelic
Overall
CADD	20.3	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 0.00401% African / African-American · 3/74,786 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,611,024 alleles · very rare exomes 2/1,458,868 · genomes 1/152,156 · joint denominator

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.Ser434Arg
Coding: c.1302C>A
MANE Select: NM_000944
dbSNP: rs369318194
Type: single nucleotide variant
Location: chr4:101032304 (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.Ser434fs Pathogenic ★ same residue
PPP3CA p.Ser434Thr Uncertain significance ★ ⚠ same residue
PPP3CA p.Ser434= 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

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-ser434arg (accessed [today's date]).

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