Is PPP3CA p.Arg73Gln (c.218G>A) pathogenic?

PPP3CA p.Arg73Gln (c.218G>A) is classified Uncertain significance in PPP3CA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.141); Ultra-rare (popmax 0.0134%, afr); Associated with developmental and epileptic encephalopathy 91.

What condition is associated with PPP3CA p.Arg73Gln (c.218G>A)?

PPP3CA p.Arg73Gln (c.218G>A) is associated with developmental and epileptic encephalopathy 91, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ClinVar).

How common is PPP3CA p.Arg73Gln (c.218G>A) in the general population?

PPP3CA p.Arg73Gln (c.218G>A) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about PPP3CA p.Arg73Gln (c.218G>A)?

AlphaMissense predicts likely benign (score 0.141) — an in-silico prediction, not a clinical call.

PPP3CA p.Arg73Gln

c.218G>A · rs141696639 · VCV1361019

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

developmental and epileptic encephalopathy 91

Computational evidence

Protein change
AlphaMissense	0.141	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -12.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 151 kb · p 0.018 · regional, not allelic
Overall
CADD	27.0	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 0.0134% African / African-American · 10/74,870 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000992% 16/1,613,698 alleles · ultra-rare exomes 9/1,461,608 · genomes 7/152,090 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,487
East Asian	0.00223%	44,880
Admixed American	0.00167%	59,962
Finnishnot grpmax-eligible	0.00156%	64,020
South Asian	0.0011%	91,036
European (non-Finnish)	0.00017%	589,936

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.Arg73Gln
Coding: c.218G>A
MANE Select: NM_000944
dbSNP: rs141696639
Type: single nucleotide variant
Location: chr4:101195957 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 73: 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.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-arg73gln (accessed [today's date]).

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