Is PPP3CA p.Leu46= (c.138A>G) pathogenic?

PPP3CA p.Leu46= (c.138A>G) is classified Benign/Likely benign in PPP3CA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-14). Very rare (popmax 0.00305%, nfe); Associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development.

How common is PPP3CA p.Leu46= (c.138A>G) in the general population?

PPP3CA p.Leu46= (c.138A>G) is very rare (popmax 0.00305%, nfe) (gnomAD).

PPP3CA p.Leu46=

Q: What condition is associated with PPP3CA p.Leu46= (c.138A>G)?

PPP3CA p.Leu46= (c.138A>G) is associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, developmental and epileptic encephalopathy 91 (ClinVar).

c.138A>G · rs143169609 · VCV1567021

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

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 1.2	GERP -0.42, phastCons 1
Overall
CADD	8.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00305% European (non-Finnish) · 36/1,179,994 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.0215% 347/1,613,916 alleles · very rare exomes 320/1,461,756 · genomes 27/152,160 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.919%	109
Remaining individualsnot grpmax-eligible	0.0592%	1,689
European (non-Finnish)grpmax	0.00305%	32,778
Finnishnot grpmax-eligible	0.00156%	64,016
African / African-American	0.00134%	74,896

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu46=
Coding: c.138A>G
MANE Select: NM_000944
dbSNP: rs143169609
Type: single nucleotide variant
Location: chr4:101196037 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 46: an α-helix

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-leu46 (accessed [today's date]).

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