Is PPARG p.Lys455Arg (c.1364A>G) pathogenic?

PPARG p.Lys455Arg (c.1364A>G) is classified Uncertain significance in PPARG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.0732); Very rare (popmax 0.00801%, afr).

How common is PPARG p.Lys455Arg (c.1364A>G) in the general population?

PPARG p.Lys455Arg (c.1364A>G) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about PPARG p.Lys455Arg (c.1364A>G)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

PPARG p.Lys455Arg

c.1364A>G · VCV4700775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K485R vs ClinVar K455R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,942 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00062% 10/1,614,104 alleles · very rare exomes 7/1,461,878 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,490
European (non-Finnish)	0.000339%	295,009

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.Lys455Arg
Coding: c.1364A>G
MANE Select: NM_138711
Type: single nucleotide variant
Location: chr3:12434081 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 485 UniProt numbering: the nr lbd domain; an α-helix

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

Similar variants

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.Pro465Leu 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
PPARG p.Arg151Gln 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-lys455arg (accessed [today's date]).

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