Is PPP3CA p.Ala451Val (c.1352C>T) pathogenic?

PPP3CA p.Ala451Val (c.1352C>T) is classified Uncertain significance in PPP3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-29). AlphaMissense: ambiguous (0.5322); Very rare (popmax 0.0011%, sas).

How common is PPP3CA p.Ala451Val (c.1352C>T) in the general population?

PPP3CA p.Ala451Val (c.1352C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PPP3CA p.Ala451Val (c.1352C>T)?

AlphaMissense predicts ambiguous (score 0.5322) — an in-silico prediction, not a clinical call.

PPP3CA p.Ala451Val

c.1352C>T · rs1330073156 · VCV1722228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5322	ambiguous
REVEL	0.276	benign-leaning
SaProt	LLR -9.45	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 170 kb · p 4.9e-41 · regional, not allelic
Overall
CADD	26.7	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 · 1/90,952 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,608,034 alleles · very rare exomes 3/1,456,106 · genomes 0/151,928 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,952
European (non-Finnish)	0.00017%	587,447

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.Ala451Val
Coding: c.1352C>T
MANE Select: NM_000944
dbSNP: rs1330073156
Type: single nucleotide variant
Location: chr4:101029183 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 451: a UniProt-annotated variant site (in iecee1; results in constitutive phosphatase activity in the absence of calmodulin); a UniProt-annotated variant site (in iecee1)

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

Similar variants

PPP3CA p.Ala451= Likely benign ★ same residue
PPP3CA c.1340-2A>G Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Ala447Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
PPP3CA p.Arg254Ser Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Asp234Glu Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Glu282Lys Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.Glu456Ter Pathogenic/Likely pathogenic ★★ same type
PPP3CA p.His92Arg Pathogenic/Likely pathogenic ★★ same type

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-ala451val (accessed [today's date]).

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