Is PPP3CA p.Asp176Val (c.527A>T) pathogenic?

PPP3CA p.Asp176Val (c.527A>T) is classified Uncertain significance in PPP3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-07). AlphaMissense: likely pathogenic (0.5773); Very rare (popmax 0.00017%, nfe).

How common is PPP3CA p.Asp176Val (c.527A>T) in the general population?

PPP3CA p.Asp176Val (c.527A>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PPP3CA p.Asp176Val (c.527A>T)?

AlphaMissense predicts likely pathogenic (score 0.5773) — an in-silico prediction, not a clinical call.

PPP3CA p.Asp176Val

c.527A>T · rs759365658 · VCV1431003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5773	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -14.65	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 2.8, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 170 kb · p 4.9e-41 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,152 alleles

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

Overall 0.000124% 2/1,610,578 alleles · very rare exomes 0/1,458,408 · genomes 2/152,170 · 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.Asp176Val
Coding: c.527A>T
MANE Select: NM_000944
dbSNP: rs759365658
Type: single nucleotide variant
Location: chr4:101098482 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 176: the 'catalytic' region; an α-helix

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

Similar variants

PPP3CA p.Asp176dup Uncertain significance ★ 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-asp176val (accessed [today's date]).

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