Is PPARA p.Ala268Val (c.803C>T) pathogenic?

PPARA p.Ala268Val (c.803C>T) is classified Likely benign in PPARA (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-08-01). AlphaMissense: ambiguous (0.3565); Rare (popmax 0.636%, nfe); Associated with PPARA-related disorder.

What condition is associated with PPARA p.Ala268Val (c.803C>T)?

PPARA p.Ala268Val (c.803C>T) is associated with PPARA-related disorder (ClinVar).

How common is PPARA p.Ala268Val (c.803C>T) in the general population?

PPARA p.Ala268Val (c.803C>T) is rare (popmax 0.636%, nfe) (gnomAD).

What do computational predictors say about PPARA p.Ala268Val (c.803C>T)?

AlphaMissense predicts ambiguous (score 0.3565) — an in-silico prediction, not a clinical call.

PPARA p.Ala268Val

c.803C>T · rs1042311 · VCV3041835

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3565 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.636%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

PPARA-related disorder

Computational evidence

Protein change
AlphaMissense	0.3565	ambiguous
REVEL	0.052	moderately benign-leaning
SaProt	LLR -4.18	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -3.3, phastCons 0.98
Regional constraint	o/e 0.67	unconstrained · MANE · 20 kb · p 5.8e-13 · regional, not allelic
Overall
CADD	20.3	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 0.636% European (non-Finnish) · 7,503/1,180,018 alleles

Filtering AF 0.624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.619%

Overall 0.527% 8,500/1,614,122 alleles · rare exomes 7,939/1,461,802 · genomes 561/152,320 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.642%	156
European (non-Finnish)grpmax	0.636%	157
Remaining individualsnot grpmax-eligible	0.478%	209
Admixed American	0.212%	473
Middle Eastern	0.149%	673
African / African-American	0.109%	915
South Asian	0.0703%	1,423
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
East Asian	0.00446%	22,440

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala268Val
Coding: c.803C>T
MANE Select: NM_005036
dbSNP: rs1042311
Type: single nucleotide variant
Location: chr22:46231883 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.18 · 79 PDB
Residue 268: the nr lbd domain; a UniProt-annotated variant site (in); an α-helix

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

Disease context

PPARA-related disorder

Similar variants

PPARA p.Pro13= Likely benign same condition
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

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-ala268val (accessed [today's date]).

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