Is PPARA p.Cys191Ser (c.571T>A) pathogenic?

PPARA p.Cys191Ser (c.571T>A) is classified Uncertain significance in PPARA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.0764); Very rare (popmax 0.00534%, afr).

How common is PPARA p.Cys191Ser (c.571T>A) in the general population?

PPARA p.Cys191Ser (c.571T>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about PPARA p.Cys191Ser (c.571T>A)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

PPARA p.Cys191Ser

c.571T>A · VCV3423307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -3.35	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 3.4	GERP -1.6, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 20 kb · p 5.8e-13 · regional, not allelic
Overall
CADD	13.47	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00534% African / African-American · 4/74,924 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,614,084 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: PPARA
Protein: p.Cys191Ser
Coding: c.571T>A
MANE Select: NM_005036
Type: single nucleotide variant
Location: chr22:46219874 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.18 · 79 PDB

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-cys191ser (accessed [today's date]).

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