NM_015869.4:c.922C>T (p.Arg308Cys) in PPARG is a missense variant present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00040%, v4.1 AF=0.00056%), meeting PM2 (moderate).1 Multiple in silico predictors (REVEL 0.441, BayesDel 0.204, SpliceAI max delta 0.00) suggest no significant deleterious impact, meeting BP4 (supporting benign).2 No variant-specific functional evidence was identified. A saturation mutagenesis study of all PPARG missense variants (PMID:27749844) tested this variant in pooled assays but did not individually report functional data for p.Arg308Cys in the published manuscript. The nearby substitution p.Arg308Pro was classified as benign.3 This variant has been reported in ClinVar as uncertain significance by a single submitter (SCV001337589, Personalized Diabetes Medicine Program) in association with monogenic diabetes. No pathogenic or benign assertion has been made by an expert panel.4 Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868), one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) do not meet the threshold for likely pathogenic (requires ≥2 moderate or 1 moderate + ≥4 supporting) or likely benign (requires ≥2 supporting benign). The variant is classified as uncertain significance (VUS).5
PPARG
Final classification
VUS
PPARG c.922C>T · p.Arg308Cys
PPARG
NM_015869.4:c.922C>T (p.Arg308Cys) in PPARG is a missense variant present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00040%, v4.1 AF=0.00056%), meeting PM2 (moderate).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
PPARG c.922C>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
5
generic_acmg_combination_rulesPMID:25741868 ↗
Gene diagram
· NM_015869.4 · variants mapped to exon structure
PPARG
NM_015869.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
This variant is present at extremely low frequency in population databases. gnomAD v2.1 reports an allele frequency of 0.00040% (1/250,872 alleles) and gnomAD v4.1 reports 0.00056% (9/1,614,096 alleles), both well below the PM2 threshold of <0.1%. No homozygotes have been observed.
gnomAD v2.1: AF=3.99e-06 (1/250872)0 homozygotes
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.441, below the 0.5 threshold for damaging prediction. BayesDel score is 0.204, below the 0.27 threshold. SpliceAI predicts no splicing impact (max delta 0.00).
REVEL: 0.441 (below 0.5 damaging threshold)BayesDel: 0.204 (below 0.27 damaging threshold)SpliceAI: max delta 0.00 (no predicted splice impact)
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with the same amino acid change (p.Arg308Cys) has been reported.
PS2
No de novo data (with confirmed maternity and paternity) are available for this variant.
PS3
No variant-specific functional evidence demonstrating a damaging effect on the gene or gene product was identified.
PS4
Insufficient case-control data available.
PM1
Although residue 308 lies within the PPARγ ligand-binding domain, it is not in a statistically significant mutational hotspot.
PM5
No pathogenic missense variant at the same amino acid residue (Arg308) was identified.
PM6
No de novo observation (without confirmation of maternity/paternity) has been reported for this variant.
PP1
No cosegregation data in affected family members are available for this variant.
PP2
While PPARG missense variants are a known mechanism for FPLD3, PPARG does not have a low rate of benign missense variation.
PP3
Multiple in silico predictors do not support a deleterious effect.
PP4
No patient-specific phenotype or family history data are available.
PP5
No reputable source reports this variant as pathogenic.
Benign
BA1
The allele frequency in gnomAD (0.00040–0.00056%) is far below the BA1 threshold of >1%.
BS1
The allele frequency in gnomAD (0.00040–0.00056%; highest subpopulation 0.00544% East Asian v2.1) is far below the BS1 threshold of >0.3%.
BS2
The variant has been observed in gnomAD (1 heterozygous carrier in v2.1, 9 in v4.1), but the phenotype of these carriers is unknown.
BS3
No variant-specific functional studies demonstrating no damaging effect on the gene product were identified.
BS4
No segregation data in affected family members are available to assess lack of segregation.
BP1
PPARG-related familial partial lipodystrophy type 3 is primarily caused by missense variants, not truncating variants.
BP2
No phasing data (in trans or in cis with another pathogenic variant) are available for this variant.
BP5
No data available demonstrating this variant in a case with an alternate molecular basis for disease.
BP6
No reputable source reports this variant as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.57588e-06; MAF= 0.00056%, 9/1614096 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22846e-05; MAF= 0.00223%, 1/44874 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.9861e-06; MAF= 0.00040%, 1/250872 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.44188e-05; MAF= 0.00544%, 1/18376 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00056%
· 9 / 1,614,096
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
East Asian 1 / 44,874 |
0.0022% |
European (non-Finnish) 8 / 1,179,976 |
0.00068% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 250,872
0 hom
0 hom
East Asian 1 / 18,376 |
0.0054% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 917446)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.441. BayesDel score = 0.204196.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PPARG, a nuclear receptor, is known to behave as an oncoprotein when fused with with PAX8 in thyroid cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55140987, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
27749844 ↗
Prospective functional classification of all possible missense variants in PPARG.
CLINVAR