Is CPT2 p.Ser22Ile (c.65G>T) pathogenic?

CPT2 p.Ser22Ile (c.65G>T) is classified Uncertain significance in CPT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-28). AlphaMissense: likely benign (0.1078); Very rare (popmax 0.00175%, nfe); Associated with carnitine palmitoyltransferase II deficiency.

What condition is associated with CPT2 p.Ser22Ile (c.65G>T)?

CPT2 p.Ser22Ile (c.65G>T) is associated with carnitine palmitoyltransferase II deficiency (ClinVar).

How common is CPT2 p.Ser22Ile (c.65G>T) in the general population?

CPT2 p.Ser22Ile (c.65G>T) is very rare (popmax 0.00175%, 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.Ser22Ile (c.65G>T)?

AlphaMissense predicts likely benign (score 0.1078) — an in-silico prediction, not a clinical call.

CPT2 p.Ser22Ile

c.65G>T · rs1057287341 · VCV2038580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

carnitine palmitoyltransferase II deficiency

Computational evidence

Protein change
AlphaMissense	0.1078	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -8.48	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 6.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	17.86	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 0.00175% European (non-Finnish) · 20/1,144,662 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000927%

Overall 0.00159% 22/1,381,308 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00175%	57,233
Remaining individualsnot grpmax-eligible	0.00168%	59,676
African / African-American	0.00138%	72,230

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.Ser22Ile
Coding: c.65G>T
MANE Select: NM_000098
dbSNP: rs1057287341
Type: single nucleotide variant
Location: chr1:53197008 (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.Ser22Asn Uncertain significance ★★ ⚠ same residue
CPT2 p.Ser22= Likely benign ★ same residue
CPT2 p.Ser22fs Pathogenic ★ same residue
CPT2 p.Ser22Cys 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

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-ser22ile (accessed [today's date]).

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