Is PPARG p.Leu375Pro (c.1124T>C) pathogenic?

PPARG p.Leu375Pro (c.1124T>C) is classified Likely pathogenic in PPARG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-15). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with PPARG-related familial partial lipodystrophy.

What condition is associated with PPARG p.Leu375Pro (c.1124T>C)?

PPARG p.Leu375Pro (c.1124T>C) is associated with PPARG-related familial partial lipodystrophy (ClinVar).

How common is PPARG p.Leu375Pro (c.1124T>C) in the general population?

PPARG p.Leu375Pro (c.1124T>C) is absent from gnomAD v4.1 (gnomAD).

How is PPARG-related familial partial lipodystrophy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PPARG p.Leu375Pro (c.1124T>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

PPARG p.Leu375Pro

c.1124T>C · rs2125285337 · VCV1341578

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PPARG-related familial partial lipodystrophy

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 8% in PPARG
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -13.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	31.0	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 L405P vs ClinVar L375P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPARG
Protein: p.Leu375Pro
Coding: c.1124T>C
MANE Select: NM_138711
dbSNP: rs2125285337
Type: single nucleotide variant
Location: chr3:12417098 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 375: the nr lbd domain; a β-strand

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

Disease context

PPARG-related familial partial lipodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For PPARG-related familial partial lipodystrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

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-leu375pro (accessed [today's date]).

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