Is PPP3CA p.Ala48Val (c.143C>T) pathogenic?

PPP3CA p.Ala48Val (c.143C>T) is classified Uncertain significance in PPP3CA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-05). AlphaMissense: likely benign (0.1304); Very rare (popmax 0.00203%, nfe).

How common is PPP3CA p.Ala48Val (c.143C>T) in the general population?

PPP3CA p.Ala48Val (c.143C>T) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about PPP3CA p.Ala48Val (c.143C>T)?

AlphaMissense predicts likely benign (score 0.1304) — an in-silico prediction, not a clinical call.

PPP3CA p.Ala48Val

c.143C>T · rs764832679 · VCV2498957

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1304 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1304	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 151 kb · p 0.018 · regional, not allelic
Overall
CADD	27.5	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 0.00203% European (non-Finnish) · 24/1,179,956 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00161% 26/1,613,884 alleles · very rare exomes 26/1,461,712 · genomes 0/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,165
African / African-American	0.00133%	74,980
South Asian	0.0011%	91,068

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.Ala48Val
Coding: c.143C>T
MANE Select: NM_000944
dbSNP: rs764832679
Type: single nucleotide variant
Location: chr4:101196032 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 48: an α-helix

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

Similar variants

PPP3CA p.Ala48Ser Uncertain significance ★ ⚠ same residue
PPP3CA p.Ala48= 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

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-ala48val (accessed [today's date]).

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