Is PPARG p.Pro465Leu (c.1394C>T) pathogenic?

PPARG p.Pro465Leu (c.1394C>T) is classified Pathogenic/Likely pathogenic in PPARG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2020-11-18). AlphaMissense: likely pathogenic (0.9788); Very rare (popmax 0.000254%, nfe); Associated with PPARG-related familial partial lipodystrophy.

What condition is associated with PPARG p.Pro465Leu (c.1394C>T)?

PPARG p.Pro465Leu (c.1394C>T) is associated with PPARG-related familial partial lipodystrophy, lipodystrophy (ClinVar).

How common is PPARG p.Pro465Leu (c.1394C>T) in the general population?

PPARG p.Pro465Leu (c.1394C>T) is very rare (popmax 0.000254%, nfe) (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.Pro465Leu (c.1394C>T)?

AlphaMissense predicts likely pathogenic (score 0.9788) — an in-silico prediction, not a clinical call.

PPARG p.Pro465Leu

c.1394C>T · rs121909244 · VCV8136

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9788 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PPARG-related familial partial lipodystrophy

Computational evidence

Protein change
AlphaMissense	0.9788	likely pathogenic ✓ concordant with ClinVar
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -11.50	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 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	29.7	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 P495L vs ClinVar P465L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,060 alleles · very rare exomes 3/1,461,878 · genomes 0/152,182 · joint denominator

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.Pro465Leu
Coding: c.1394C>T
MANE Select: NM_138711
dbSNP: rs121909244
Type: single nucleotide variant
Location: chr3:12434111 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 495 UniProt numbering: the nr lbd domain; a UniProt-annotated variant site (in diabetes); an α-helix

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

Disease context

Also linked: lipodystrophy

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.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
PPARG p.Ser380Arg 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-pro465leu (accessed [today's date]).

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