Is PPARA p.Ala381Pro (c.1141G>C) pathogenic?

PPARA p.Ala381Pro (c.1141G>C) is classified Uncertain significance in PPARA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1.

How common is PPARA p.Ala381Pro (c.1141G>C) in the general population?

PPARA p.Ala381Pro (c.1141G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPARA p.Ala381Pro (c.1141G>C)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

PPARA p.Ala381Pro

c.1141G>C · VCV4570677

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic · top 10% in PPARA
REVEL	0.621	indeterminate
SaProt	LLR -12.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 20 kb · p 5.8e-13 · regional, not allelic
Overall
CADD	29.3	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPARA
Protein: p.Ala381Pro
Coding: c.1141G>C
MANE Select: NM_005036
Type: single nucleotide variant
Location: chr22:46232221 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.18 · 79 PDB
Residue 381: the nr lbd domain; an α-helix; the 'required for heterodimerization with rxra' 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.Arg141His 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-ala381pro (accessed [today's date]).

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