Is PPARG p.Arg286His (c.857G>A) pathogenic?

PPARG p.Arg286His (c.857G>A) is classified Uncertain significance in PPARG (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-18). AlphaMissense: ambiguous (0.3814); Very rare (popmax 0.00288%, nfe); Associated with PPARG-related disorder.

What condition is associated with PPARG p.Arg286His (c.857G>A)?

PPARG p.Arg286His (c.857G>A) is associated with PPARG-related disorder, colon carcinoma (ClinVar).

How common is PPARG p.Arg286His (c.857G>A) in the general population?

PPARG p.Arg286His (c.857G>A) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about PPARG p.Arg286His (c.857G>A)?

AlphaMissense predicts ambiguous (score 0.3814) — an in-silico prediction, not a clinical call.

PPARG p.Arg286His

c.857G>A · rs28936407 · VCV8135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Conditions

PPARG-related disorder

Computational evidence

Protein change
AlphaMissense	0.3814	ambiguous
REVEL	0.428	indeterminate
SaProt	LLR -7.29	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	27.5	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 R316H vs ClinVar R286H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00288% European (non-Finnish) · 34/1,180,016 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00235% 38/1,614,014 alleles · very rare exomes 35/1,461,834 · genomes 3/152,180 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,706
East Asian	0.00223%	44,890
South Asian	0.0022%	45,539
Admixed American	0.00167%	60,004

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.Arg286His
Coding: c.857G>A
MANE Select: NM_138711
dbSNP: rs28936407
Type: single nucleotide variant
Location: chr3:12416831 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 316 UniProt numbering: the nr lbd domain; a UniProt-annotated variant site (in colon cancer; sporadic; somatic mutation; partial loss of ligand-binding); an α-helix; a binding site

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

Disease context

PPARG-related disorder

Also linked: colon carcinoma

Similar variants

PPARG p.Pro83Gln Uncertain significance ★★ ⚠ same condition
PPARG p.Tyr143Cys Uncertain significance ★★ ⚠ same condition
PPARG p.Val111Ile Uncertain significance ★★ same condition
PPARG c.730-2A>G Likely pathogenic ★ same condition
PPARG p.Gln435Ter Likely pathogenic ★ same condition
PPARG p.Arg134Pro Uncertain significance ★ ⚠ same condition
PPARG p.Leu450Pro Uncertain significance ★ ⚠ same condition
PPARG p.Tyr248His 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-arg286his (accessed [today's date]).

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