Is PPARG p.Ser380Arg (c.1140C>A) pathogenic?

PPARG p.Ser380Arg (c.1140C>A) is classified Uncertain significance in PPARG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.8814); Very rare (popmax 0.00667%, amr); Associated with lipodystrophy.

What condition is associated with PPARG p.Ser380Arg (c.1140C>A)?

PPARG p.Ser380Arg (c.1140C>A) is associated with lipodystrophy (ClinVar).

How common is PPARG p.Ser380Arg (c.1140C>A) in the general population?

PPARG p.Ser380Arg (c.1140C>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PPARG p.Ser380Arg (c.1140C>A)?

AlphaMissense predicts likely pathogenic (score 0.8814) — an in-silico prediction, not a clinical call.

PPARG p.Ser380Arg

c.1140C>A · rs148844673 · VCV2175684

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lipodystrophy

Computational evidence

Protein change
AlphaMissense	0.8814	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -9.73	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -4.4
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S410R vs ClinVar S380R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,996 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00149% 24/1,613,896 alleles · very rare exomes 18/1,461,790 · genomes 6/152,106 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00153%	65,554

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.Ser380Arg
Coding: c.1140C>A
MANE Select: NM_138711
dbSNP: rs148844673
Type: single nucleotide variant
Location: chr3:12417114 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 410 UniProt numbering: the nr lbd domain; an α-helix

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

Disease context

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

Similar variants

PPARG p.Ser380= Likely benign same residue
PPARG p.Pro465Leu Pathogenic/Likely pathogenic ★★ same condition
PPARG p.Arg164Gln Likely pathogenic ★★ same type
PPARG p.Arg395Cys Pathogenic/Likely pathogenic ★★ same type
PPARG p.Arg395His Pathogenic/Likely pathogenic ★★ same type
PPARG p.Tyr121Cys Pathogenic/Likely pathogenic ★★ same type
PPARG c.-8A>G Uncertain significance ★★ ⚠ same type
PPARG p.Arg110His Uncertain significance ★★ ⚠ same type

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-ser380arg (accessed [today's date]).

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