Is PPP3CA p.Ala473Ser (c.1417G>T) pathogenic?

PPP3CA p.Ala473Ser (c.1417G>T) is classified Pathogenic in PPP3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-29). AlphaMissense: likely pathogenic (0.8771); Absent from gnomAD v4.1; Associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development.

How common is PPP3CA p.Ala473Ser (c.1417G>T) in the general population?

PPP3CA p.Ala473Ser (c.1417G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP3CA p.Ala473Ser (c.1417G>T)?

AlphaMissense predicts likely pathogenic (score 0.8771) — an in-silico prediction, not a clinical call.

PPP3CA p.Ala473Ser

Q: What condition is associated with PPP3CA p.Ala473Ser (c.1417G>T)?

PPP3CA p.Ala473Ser (c.1417G>T) is associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ClinVar).

c.1417G>T · rs1560567337 · VCV1064703

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8771 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Computational evidence

Protein change
AlphaMissense	0.8771	likely pathogenic ✓ concordant with ClinVar
REVEL	0.262	benign-leaning
SaProt	LLR -6.84	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 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 170 kb · p 4.9e-41 · regional, not allelic
Overall
CADD	24.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPP3CA
Protein: p.Ala473Ser
Coding: c.1417G>T
MANE Select: NM_000944
dbSNP: rs1560567337
Type: single nucleotide variant
Location: chr4:101026014 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 473: a UniProt-annotated variant site (in iecee1; results in constitutive phosphatase activity in the absence of calmodulin); a UniProt-annotated variant site (in iecee1); a UniProt-annotated variant site (in acciid); the 'autoinhibitory domain' region; 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

Similar variants

PPP3CA p.Ala473Thr Pathogenic ★ ⚠ same residue
PPP3CA p.Glu282Lys Pathogenic/Likely pathogenic ★★ same condition
PPP3CA c.860+3G>A Uncertain significance ★★ same condition
PPP3CA p.Arg28Trp Uncertain significance ★★ same condition
PPP3CA p.Arg42Cys Uncertain significance ★★ ⚠ same condition
PPP3CA p.Arg42His Uncertain significance ★★ ⚠ same condition
PPP3CA p.Arg478Gln Uncertain significance ★★ ⚠ same condition
PPP3CA p.Arg73Gln 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-ala473ser (accessed [today's date]).

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