Is PPARG p.Ser427= (c.1281A>G) pathogenic?

PPARG p.Ser427= (c.1281A>G) is classified Benign/Likely benign in PPARG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-08). Low-frequency (popmax 2.01%, afr); Associated with obesity disorder.

What condition is associated with PPARG p.Ser427= (c.1281A>G)?

PPARG p.Ser427= (c.1281A>G) is associated with obesity disorder, type 2 diabetes mellitus, PPARG-related familial partial lipodystrophy (ClinVar).

How common is PPARG p.Ser427= (c.1281A>G) in the general population?

PPARG p.Ser427= (c.1281A>G) is low-frequency (popmax 2.01%, afr) (gnomAD).

PPARG p.Ser427=

c.1281A>G · rs41516544 · VCV343049

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.01%, afr)

Conditions

obesity disorder

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
Constraint at this position
Conservation	phyloP -4.4	GERP -4.2
Overall
CADD	0.298	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.01% African / African-American · 1,510/75,056 alleles

Filtering AF 1.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.89%

Overall 0.112% 1,801/1,614,222 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.01%	50
Remaining individualsnot grpmax-eligible	0.219%	456
Admixed American	0.173%	577
Middle Eastern	0.0825%	1,212
East Asian	0.0156%	6,413
European (non-Finnish)	0.00305%	32,779
South Asian	0.0022%	45,540

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.Ser427=
Coding: c.1281A>G
MANE Select: NM_138711
dbSNP: rs41516544
Type: single nucleotide variant
Location: chr3:12433998 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 427: the nr lbd domain; a β-strand

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

Disease context

obesity disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus 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-ser427 (accessed [today's date]).

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