Is PPP3CA p.Ile277Val (c.829A>G) pathogenic?

PPP3CA p.Ile277Val (c.829A>G) is classified Uncertain significance in PPP3CA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0711); Very rare (popmax 0.00289%, nfe); Associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development.

How common is PPP3CA p.Ile277Val (c.829A>G) in the general population?

PPP3CA p.Ile277Val (c.829A>G) is very rare (popmax 0.00289%, nfe) (gnomAD).

What do computational predictors say about PPP3CA p.Ile277Val (c.829A>G)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

PPP3CA p.Ile277Val

Q: What condition is associated with PPP3CA p.Ile277Val (c.829A>G)?

PPP3CA p.Ile277Val (c.829A>G) is associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, developmental and epileptic encephalopathy 91 (ClinVar).

c.829A>G · rs540250871 · VCV1369039

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00289%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -5.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00289% European (non-Finnish) · 34/1,175,832 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00184%

Overall 0.00224% 36/1,606,152 alleles · very rare exomes 34/1,453,982 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00289%	34,583
African / African-American	0.00268%	37,251

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.Ile277Val
Coding: c.829A>G
MANE Select: NM_000944
dbSNP: rs540250871
Type: single nucleotide variant
Location: chr4:101083217 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 21 PDB
Residue 277: the 'catalytic' region; a β-strand

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

Disease context

arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy 91

Similar variants

PPP3CA p.Ile277Met Uncertain significance ★ same residue
PPP3CA p.Ala447Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PPP3CA p.Arg254Ser Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Asp234Glu Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.Glu282Lys Pathogenic/Likely pathogenic ★★ same condition
PPP3CA p.His92Arg Pathogenic/Likely pathogenic ★★ same condition
PPP3CA c.860+3G>A Uncertain significance ★★ same condition
PPP3CA p.Arg28Gln Uncertain significance ★★ ⚠ 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-ile277val (accessed [today's date]).

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