Is PPP3CA p.Val174= (c.522A>G) pathogenic?

PPP3CA p.Val174= (c.522A>G) is classified Likely benign in PPP3CA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-14). Very rare (popmax 0.000255%, nfe); Associated with PPP3CA-related disorder.

What condition is associated with PPP3CA p.Val174= (c.522A>G)?

PPP3CA p.Val174= (c.522A>G) is associated with PPP3CA-related disorder (ClinVar).

How common is PPP3CA p.Val174= (c.522A>G) in the general population?

PPP3CA p.Val174= (c.522A>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

PPP3CA p.Val174=

c.522A>G · VCV3351452

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

PPP3CA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -5.6
Overall
CADD	0.304	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,177,660 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,609,546 alleles · very rare exomes 3/1,457,236 · genomes 0/152,310 · joint denominator

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.Val174=
Coding: c.522A>G
MANE Select: NM_000944
Type: single nucleotide variant
Location: chr4:101098487 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 174: the 'catalytic' region; an α-helix

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

Disease context

PPP3CA-related disorder

Similar variants

PPP3CA p.Val174Ala Uncertain significance ★ ⚠ same residue
PPP3CA p.Val174Ile Uncertain significance ★ ⚠ 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.His281Arg Likely pathogenic ★ same condition
PPP3CA p.Asp38Gly Uncertain significance ★ ⚠ same condition
PPP3CA p.Arg55= 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-val174 (accessed [today's date]).

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