Is PPARG p.Pro424fs (c.1271del) pathogenic?

PPARG p.Pro424fs (c.1271del) is classified Pathogenic in PPARG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-30). Very rare (popmax 0.00333%, amr); Associated with PPARG-related disorder.

What condition is associated with PPARG p.Pro424fs (c.1271del)?

PPARG p.Pro424fs (c.1271del) is associated with PPARG-related disorder, PPARG-related familial partial lipodystrophy (ClinVar).

How common is PPARG p.Pro424fs (c.1271del) in the general population?

PPARG p.Pro424fs (c.1271del) is very rare (popmax 0.00333%, amr) (gnomAD).

PPARG p.Pro424fs

c.1271del · rs770557781 · VCV436405

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

PPARG-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,018 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000274% 4/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,009
European (non-Finnish)	0.000169%	590,016

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.Pro424fs
Coding: c.1271del
MANE Select: NM_138711
dbSNP: rs770557781
Type: Deletion
Location: chr3:12433986 (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

Disease context

PPARG-related disorder

Also linked: PPARG-related familial partial lipodystrophy

Similar variants

PPARG c.-8-28082del Likely pathogenic ★ same condition
PPARG p.Ala276fs Likely pathogenic ★ same condition
PPARG p.Pro424Ala Uncertain significance ★ ⚠ same residue
PPARG p.Tyr162_Arg164del Uncertain significance same condition
PPARG p.Arg164Gln Likely pathogenic ★★ same condition
PPARG p.Arg395Cys Pathogenic/Likely pathogenic ★★ same condition
PPARG p.Arg395His Pathogenic/Likely pathogenic ★★ same condition
PPARG p.Pro465Leu Pathogenic/Likely pathogenic ★★ 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/pparg-p-pro424fs (accessed [today's date]).

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