Is PPARG p.Val22Ile (c.64G>A) pathogenic?

PPARG p.Val22Ile (c.64G>A) is classified Likely benign in PPARG (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0659); Ultra-rare (popmax 0.04%, afr).

How common is PPARG p.Val22Ile (c.64G>A) in the general population?

PPARG p.Val22Ile (c.64G>A) is ultra-rare (popmax 0.04%, afr) (gnomAD).

What do computational predictors say about PPARG p.Val22Ile (c.64G>A)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

PPARG p.Val22Ile

c.64G>A · rs149324518 · VCV2634503

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.56	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 0.64	GERP -0.034, phastCons 0.028
Regional constraint	o/e 1.02	unconstrained · MANE · 1,711 bp · p 0.78 · regional, not allelic
Overall
CADD	11.86	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 V52I vs ClinVar V22I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% African / African-American · 30/74,912 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00297% 48/1,613,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,497
Admixed American	0.005%	19,989
East Asian	0.00446%	22,435
South Asian	0.00439%	22,771
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000678%	147,495

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.Val22Ile
Coding: c.64G>A
MANE Select: NM_138711
dbSNP: rs149324518
Type: single nucleotide variant
Location: chr3:12379775 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB

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-val22ile (accessed [today's date]).

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