Is CPT2 p.Arg503His (c.1508G>A) pathogenic?

CPT2 p.Arg503His (c.1508G>A) is classified Uncertain significance in CPT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-22). AlphaMissense: likely pathogenic (0.803); Very rare (popmax 0.00447%, eas); Associated with carnitine palmitoyltransferase II deficiency.

What condition is associated with CPT2 p.Arg503His (c.1508G>A)?

CPT2 p.Arg503His (c.1508G>A) is associated with carnitine palmitoyltransferase II deficiency (ClinVar).

How common is CPT2 p.Arg503His (c.1508G>A) in the general population?

CPT2 p.Arg503His (c.1508G>A) is very rare (popmax 0.00447%, eas) (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.Arg503His (c.1508G>A)?

AlphaMissense predicts likely pathogenic (score 0.803) — an in-silico prediction, not a clinical call.

CPT2 p.Arg503His

c.1508G>A · rs750079911 · VCV297608

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carnitine palmitoyltransferase II deficiency

Computational evidence

Protein change
AlphaMissense	0.803	likely pathogenic
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -11.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00447% East Asian · 2/44,782 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000435% 7/1,608,480 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,391
South Asian	0.0011%	90,588
European (non-Finnish)	0.00034%	294,053

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.Arg503His
Coding: c.1508G>A
MANE Select: NM_000098
dbSNP: rs750079911
Type: single nucleotide variant
Location: chr1:53211182 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.52
Residue 503: a UniProt-annotated variant site (in cpt2d)

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.Arg503Cys Pathogenic/Likely pathogenic ★★ same residue
CPT2 p.Arg503= 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-arg503his (accessed [today's date]).

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