Is CPT2 p.Phe417Leu (c.1251C>G) pathogenic?

CPT2 p.Phe417Leu (c.1251C>G) is classified Uncertain significance in CPT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-02-02). AlphaMissense: likely pathogenic (0.8891); Very rare (popmax 8.47e-05%, nfe); Associated with carnitine palmitoyltransferase II deficiency.

What condition is associated with CPT2 p.Phe417Leu (c.1251C>G)?

CPT2 p.Phe417Leu (c.1251C>G) is associated with carnitine palmitoyltransferase II deficiency (ClinVar).

How common is CPT2 p.Phe417Leu (c.1251C>G) in the general population?

CPT2 p.Phe417Leu (c.1251C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Carnitine palmitoyltransferase II deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CPT2 p.Phe417Leu (c.1251C>G)?

AlphaMissense predicts likely pathogenic (score 0.8891) — an in-silico prediction, not a clinical call.

CPT2 p.Phe417Leu

c.1251C>G · rs576822710 · VCV2061386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carnitine palmitoyltransferase II deficiency

Computational evidence

Protein change
AlphaMissense	0.8891	likely pathogenic
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -8.89	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.28	GERP -0.69, phastCons 0.028
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	21.1	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 0.000657% 1/152,168 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: CPT2
Protein: p.Phe417Leu
Coding: c.1251C>G
MANE Select: NM_000098
dbSNP: rs576822710
Type: single nucleotide variant
Location: chr1:53210925 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.52

Full CPT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

carnitine palmitoyltransferase II deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Carnitine palmitoyltransferase II deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CPT2 p.Phe417= Likely benign ★★ same residue
CPT2 c.340+1G>C Pathogenic/Likely pathogenic ★★ same condition
CPT2 c.340+5G>A Likely pathogenic ★★ same condition
CPT2 c.341-2A>G Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.Ala67Gly Likely pathogenic ★★ ⚠ same condition
CPT2 p.Arg124Gln Likely pathogenic ★★ ⚠ same condition
CPT2 p.Arg124Ter Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.Arg151Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition

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/cpt2-p-phe417leu (accessed [today's date]).

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