Is PPARG p.Ala116= (c.348T>C) pathogenic?

PPARG p.Ala116= (c.348T>C) is classified Conflicting classifications of pathogenicity in PPARG (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). Rare (popmax 0.859%, mid); Associated with INSULIN RESISTANCE, DIGENIC.

What condition is associated with PPARG p.Ala116= (c.348T>C)?

PPARG p.Ala116= (c.348T>C) is associated with INSULIN RESISTANCE, DIGENIC, obesity disorder, PPARG-related familial partial lipodystrophy (ClinVar).

How common is PPARG p.Ala116= (c.348T>C) in the general population?

PPARG p.Ala116= (c.348T>C) is rare (popmax 0.859%, mid) (gnomAD).

PPARG p.Ala116=

c.348T>C · rs147975759 · VCV342922

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.859%, mid)

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
Constraint at this position
Conservation	phyloP -2.5	GERP -3.8
Overall
CADD	5.662	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.859% Middle Eastern · 52/6,056 alleles

Filtering AF 0.673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.606%

Overall 0.0395% 638/1,613,664 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.859%	116
Admixed American	0.214%	468
Ashkenazi Jewishnot grpmax-eligible	0.135%	740
Remaining individualsnot grpmax-eligible	0.102%	976
South Asian	0.0659%	1,518
African / African-American	0.04%	2,500
European (non-Finnish)	0.0224%	4,469

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.Ala116=
Coding: c.348T>C
MANE Select: NM_138711
dbSNP: rs147975759
Type: single nucleotide variant
Location: chr3:12381449 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB

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.Ala116fs Likely pathogenic ★ same residue
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

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-ala116 (accessed [today's date]).

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