Is PPARG p.Val111Ile (c.331G>A) pathogenic?

PPARG p.Val111Ile (c.331G>A) is classified Uncertain significance in PPARG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-07). AlphaMissense: ambiguous (0.5075); Ultra-rare (popmax 0.0494%, mid); Associated with PPARG-related disorder.

What condition is associated with PPARG p.Val111Ile (c.331G>A)?

PPARG p.Val111Ile (c.331G>A) is associated with PPARG-related disorder (ClinVar).

How common is PPARG p.Val111Ile (c.331G>A) in the general population?

PPARG p.Val111Ile (c.331G>A) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about PPARG p.Val111Ile (c.331G>A)?

AlphaMissense predicts ambiguous (score 0.5075) — an in-silico prediction, not a clinical call.

PPARG p.Val111Ile

c.331G>A · rs762777341 · VCV2634817

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Conditions

PPARG-related disorder

Computational evidence

Protein change
AlphaMissense	0.5075	ambiguous
REVEL	0.524	indeterminate
SaProt	LLR -5.09	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	23.8	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 V141I vs ClinVar V111I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% Middle Eastern · 3/6,078 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00062% 10/1,613,530 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,026
European (non-Finnish)	0.000593%	168,543

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.Val111Ile
Coding: c.331G>A
MANE Select: NM_138711
dbSNP: rs762777341
Type: single nucleotide variant
Location: chr3:12381432 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 141 UniProt numbering: a DNA-binding region; a β-strand

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

Disease context

PPARG-related disorder

Similar variants

PPARG p.Pro83Gln Uncertain significance ★★ ⚠ same condition
PPARG p.Tyr143Cys 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.Arg286His 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-val111ile (accessed [today's date]).

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