Is PPARG p.Ile454= (c.1362C>T) pathogenic?

PPARG p.Ile454= (c.1362C>T) is classified Benign/Likely benign in PPARG (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-01). Rare (popmax 0.435%, nfe); Associated with INSULIN RESISTANCE, DIGENIC.

What condition is associated with PPARG p.Ile454= (c.1362C>T)?

PPARG p.Ile454= (c.1362C>T) is associated with INSULIN RESISTANCE, DIGENIC, obesity disorder, PPARG-related familial partial lipodystrophy (ClinVar).

How common is PPARG p.Ile454= (c.1362C>T) in the general population?

PPARG p.Ile454= (c.1362C>T) is rare (popmax 0.435%, nfe) (gnomAD).

PPARG p.Ile454=

c.1362C>T · rs149367249 · VCV343050

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.435%, nfe)

Conditions

INSULIN RESISTANCE, DIGENIC

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
Pangolin	Δ0.20	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.34	GERP -4.6, phastCons 0.9
Overall
CADD	5.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.435% European (non-Finnish) · 5,134/1,180,020 alleles

Filtering AF 0.425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.421%

Overall 0.353% 5,693/1,614,184 alleles · rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.504%	198
European (non-Finnish)grpmax	0.435%	230
Finnishnot grpmax-eligible	0.201%	496
Ashkenazi Jewishnot grpmax-eligible	0.182%	548
African / African-American	0.0586%	1,706
Middle Eastern	0.0495%	2,021
Admixed American	0.0233%	4,287

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile454=
Coding: c.1362C>T
MANE Select: NM_138711
dbSNP: rs149367249
Type: single nucleotide variant
Location: chr3:12434079 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 454: the nr lbd domain; a β-strand

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

Disease context

INSULIN RESISTANCE, DIGENIC — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: obesity disorder PPARG-related familial partial lipodystrophy

Similar variants

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
PPARG p.Tyr121Cys Pathogenic/Likely pathogenic ★★ same condition
PPARG p.Asp144Gly Uncertain significance ★★ ⚠ same condition
PPARG p.Met105Ile Uncertain significance ★★ ⚠ same condition
PPARG p.Pro83Gln 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/pparg-p-ile454 (accessed [today's date]).

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