Is PPP3CA p.His281Arg (c.842A>G) pathogenic?

PPP3CA p.His281Arg (c.842A>G) is classified Likely pathogenic in PPP3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with PPP3CA-related disorder.

What condition is associated with PPP3CA p.His281Arg (c.842A>G)?

PPP3CA p.His281Arg (c.842A>G) is associated with PPP3CA-related disorder (ClinVar).

How common is PPP3CA p.His281Arg (c.842A>G) in the general population?

PPP3CA p.His281Arg (c.842A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPP3CA p.His281Arg (c.842A>G)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

PPP3CA p.His281Arg

c.842A>G · VCV4967923

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PPP3CA-related disorder

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 7% in PPP3CA
REVEL	0.974	strongly pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 170 kb · p 4.9e-41 · regional, not allelic
Overall
CADD	25.6	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.His281Arg
Coding: c.842A>G
MANE Select: NM_000944
Type: single nucleotide variant
Location: chr4:101083204 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 281: the 'catalytic' region; a binding site; a UniProt-annotated variant site (in iecee1)

Full PPP3CA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PPP3CA-related disorder

Similar variants

PPP3CA p.His281Gln Likely pathogenic ★ same residue
PPP3CA p.His281= Likely benign ★ same residue
PPP3CA p.Glu282Lys Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Asp36Asn Uncertain significance ★★ ⚠ same condition
PPP3CA p.Ser2Cys Uncertain significance ★★ ⚠ same condition
PPP3CA p.Asp38Gly Uncertain significance ★ ⚠ same condition
PPP3CA p.Arg55= Likely benign same condition
PPP3CA p.Val174= Likely benign 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-his281arg (accessed [today's date]).

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