Is PPP3CA p.Arg28Trp (c.82C>T) pathogenic?

PPP3CA p.Arg28Trp (c.82C>T) is classified Uncertain significance in PPP3CA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-20). AlphaMissense: ambiguous (0.4932); Very rare (popmax 0.0011%, sas); Associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development.

How common is PPP3CA p.Arg28Trp (c.82C>T) in the general population?

PPP3CA p.Arg28Trp (c.82C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PPP3CA p.Arg28Trp (c.82C>T)?

AlphaMissense predicts ambiguous (score 0.4932) — an in-silico prediction, not a clinical call.

PPP3CA p.Arg28Trp

Q: What condition is associated with PPP3CA p.Arg28Trp (c.82C>T)?

PPP3CA p.Arg28Trp (c.82C>T) is associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, developmental and epileptic encephalopathy 91 (ClinVar).

c.82C>T · rs770562478 · VCV1408404

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Computational evidence

Protein change
AlphaMissense	0.4932	ambiguous
REVEL	0.378	indeterminate
SaProt	LLR -17.09	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 151 kb · p 0.018 · regional, not allelic
Overall
CADD	33.0	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 0.0011% South Asian · 1/91,060 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,734 alleles · very rare exomes 5/1,461,598 · genomes 0/152,136 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,060
European (non-Finnish)	0.000339%	294,977

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.Arg28Trp
Coding: c.82C>T
MANE Select: NM_000944
dbSNP: rs770562478
Type: single nucleotide variant
Location: chr4:101196093 (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.Arg28Gln 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
PPP3CA p.His92Arg Pathogenic/Likely pathogenic ★★ same condition
PPP3CA c.860+3G>A Uncertain significance ★★ same condition
PPP3CA p.Arg42Cys 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-arg28trp (accessed [today's date]).

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