Is PPARA p.Lys147Arg (c.440A>G) pathogenic?

PPARA p.Lys147Arg (c.440A>G) is classified Uncertain significance in PPARA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.1738); Ultra-rare (popmax 0.0111%, eas).

How common is PPARA p.Lys147Arg (c.440A>G) in the general population?

PPARA p.Lys147Arg (c.440A>G) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about PPARA p.Lys147Arg (c.440A>G)?

AlphaMissense predicts likely benign (score 0.1738) — an in-silico prediction, not a clinical call.

PPARA p.Lys147Arg

c.440A>G · rs750956786 · VCV2484135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1738	likely benign
REVEL	0.737	pathogenic-leaning
SaProt	LLR -7.76	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 20 kb · p 5.8e-13 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,898 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00031% 5/1,614,026 alleles · ultra-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: PPARA
Protein: p.Lys147Arg
Coding: c.440A>G
MANE Select: NM_005036
dbSNP: rs750956786
Type: single nucleotide variant
Location: chr22:46218333 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.18 · 79 PDB
Residue 147: a DNA-binding region

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

Similar variants

PPARA p.Asn235= Benign ★★ same type
PPARA p.Leu184= Benign ★★ same type
PPARA p.Val227Ala Benign ★★ same type
PPARA p.Ala186Val Uncertain significance ★ same type
PPARA p.Ala201Thr Uncertain significance ★ ⚠ same type
PPARA p.Ala225Thr Uncertain significance ★ ⚠ same type
PPARA p.Ala291Thr Uncertain significance ★ ⚠ same type
PPARA p.Ala381Pro 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/ppara-p-lys147arg (accessed [today's date]).

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