Is CPT2 p.Arg219Trp (c.655C>T) pathogenic?

CPT2 p.Arg219Trp (c.655C>T) is classified Uncertain significance in CPT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-31). AlphaMissense: likely benign (0.2804); Very rare (popmax 0.00144%, nfe); Associated with carnitine palmitoyltransferase II deficiency.

What condition is associated with CPT2 p.Arg219Trp (c.655C>T)?

CPT2 p.Arg219Trp (c.655C>T) is associated with carnitine palmitoyltransferase II deficiency (ClinVar).

How common is CPT2 p.Arg219Trp (c.655C>T) in the general population?

CPT2 p.Arg219Trp (c.655C>T) is very rare (popmax 0.00144%, 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.Arg219Trp (c.655C>T)?

AlphaMissense predicts likely benign (score 0.2804) — an in-silico prediction, not a clinical call.

CPT2 p.Arg219Trp

c.655C>T · rs367691827 · VCV863218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2804 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carnitine palmitoyltransferase II deficiency

Computational evidence

Protein change
AlphaMissense	0.2804	likely benign
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -11.04	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	29.8	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 0.00144% European (non-Finnish) · 17/1,180,040 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.00144%	69,414
South Asian	0.0011%	91,088

Remaining individuals 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: CPT2
Protein: p.Arg219Trp
Coding: c.655C>T
MANE Select: NM_000098
dbSNP: rs367691827
Type: single nucleotide variant
Location: chr1:53210329 (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.Arg219Gln Uncertain significance ★★ ⚠ same residue
CPT2 p.Arg219= 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

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-arg219trp (accessed [today's date]).

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