Is PPARG p.Pro424Ala (c.1270C>G) pathogenic?

PPARG p.Pro424Ala (c.1270C>G) is classified Uncertain significance in PPARG (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.2794); Ultra-rare (popmax 0.0333%, amr).

How common is PPARG p.Pro424Ala (c.1270C>G) in the general population?

PPARG p.Pro424Ala (c.1270C>G) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about PPARG p.Pro424Ala (c.1270C>G)?

AlphaMissense predicts likely benign (score 0.2794) — an in-silico prediction, not a clinical call.

PPARG p.Pro424Ala

c.1270C>G · VCV3352409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2794	likely benign
REVEL	0.689	pathogenic-leaning
SaProt	LLR -9.53	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P454A vs ClinVar P424A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,012 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00322% 52/1,614,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,001
African / African-American	0.00934%	10,705
Remaining individualsnot grpmax-eligible	0.0032%	31,245
South Asian	0.0022%	45,538
European (non-Finnish)	0.00178%	56,193

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: PPARG
Protein: p.Pro424Ala
Coding: c.1270C>G
MANE Select: NM_138711
Type: single nucleotide variant
Location: chr3:12433987 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 424: the nr lbd domain; a β-strand

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

Similar variants

PPARG p.Pro424fs Pathogenic ★★ same residue
PPARG p.Arg164Gln Likely pathogenic ★★ same type
PPARG p.Arg395Cys Pathogenic/Likely pathogenic ★★ same type
PPARG p.Arg395His Pathogenic/Likely pathogenic ★★ same type
PPARG p.Pro465Leu Pathogenic/Likely pathogenic ★★ same type
PPARG p.Tyr121Cys Pathogenic/Likely pathogenic ★★ same type
PPARG c.-8A>G Uncertain significance ★★ ⚠ same type
PPARG p.Arg110His Uncertain significance ★★ ⚠ 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/pparg-p-pro424ala (accessed [today's date]).

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