Is PPARG p.Phe358Cys (c.1073T>G) pathogenic?

PPARG p.Phe358Cys (c.1073T>G) is classified Uncertain significance in PPARG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely pathogenic (0.9657); Very rare (popmax 6.85e-05%).

How common is PPARG p.Phe358Cys (c.1073T>G) in the general population?

PPARG p.Phe358Cys (c.1073T>G) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about PPARG p.Phe358Cys (c.1073T>G)?

AlphaMissense predicts likely pathogenic (score 0.9657) — an in-silico prediction, not a clinical call.

PPARG p.Phe358Cys

c.1073T>G · VCV4961361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9657	likely pathogenic
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -11.81	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 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 53 kb · p 1.2e-17 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 F388C vs ClinVar F358C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.85e-05%

Overall 6.85e-05% 1/1,460,786 alleles · very rare

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.Phe358Cys
Coding: c.1073T>G
MANE Select: NM_138711
Type: single nucleotide variant
Location: chr3:12417047 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 76.11 · 321 PDB
Residue 358: 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.Phe358Leu Pathogenic ⚠ same residue
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

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-phe358cys (accessed [today's date]).

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