# NM_000098.3(CPT2):c.1152del (p.Phe384fs)

https://sugi.bio/variant/cpt2-p-phe384fs

## Summary

**CPT2 p.Phe384fs (c.1152del)** is classified **Pathogenic** in CPT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-28). Very rare (popmax 0.00223%, eas); Associated with carnitine palmitoyltransferase II deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1414678698 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CPT2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to carnitine palmitoyltransferase II deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CPT2 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Carnitine palmitoyltransferase II deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Muscle weakness — Very frequent (99-80%)
- Myalgia — Very frequent (99-80%)
- Reduced carnitine O-palmitoyltransferase activity — Very frequent (99-80%)
- Myoglobinuria — Frequent (79-30%)
- Hyperlipidemia — Frequent (79-30%)
- Myopathy — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Exercise intolerance — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001121/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPT2](https://sugi.bio/atlas/gene/CPT2/) |
| Protein change (HGVS p.) | p.Phe384fs |
| Coding change (HGVS c.) | c.1152del |
| MANE Select transcript | [NM_000098](https://www.ncbi.nlm.nih.gov/nuccore/NM_000098) |
| dbSNP | [rs1414678698](https://www.ncbi.nlm.nih.gov/snp/rs1414678698/) |
| Variant type | Deletion |
| Location | chr1:53210821-53210821 (GRCh38) |
| ClinVar | [VCV2731936](https://www.ncbi.nlm.nih.gov/clinvar/variation/2731936/) |

**All HGVS expressions:** `NC_000001.10:g.53676498del`, `NC_000001.11:g.53210826del`, `NG_008035.1:g.19398del`, `NM_000098.3:c.1152del`, `NM_001330589.2:c.1152del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.262, GERP -0.803, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.038, pLI 1.9677e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 5**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,872 in the highest group · 1/1,461,884 alleles overall — very rare (popmax 0.00223%, eas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CPT2** population constraint: LOEUF 1.038, pLI 1.9677e-09, missense-Z 0.75528. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **carnitine palmitoyltransferase II deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.52, 93% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CPT2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CPT2's established molecular role includes carnitine O-palmitoyltransferase activity.


### Pathways affected {#pathways}

CPT2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Carnitine shuttle](https://reactome.org/content/detail/R-HSA-200425) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** carnitine O-palmitoyltransferase activity, acyltransferase activity.

**Biological process:** long-chain fatty acid metabolic process, fatty acid beta-oxidation, carnitine metabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-28.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-28 |

## Associated conditions {#conditions}

[carnitine palmitoyltransferase II deficiency](https://sugi.bio/atlas/disease/carnitine-palmitoyltransferase-ii-deficiency/).

**Reported phenotype names (ClinVar):** Carnitine palmitoyltransferase II deficiency, Carnitine Palmitoyltransferase 2 Deficiency.

## Similar variants {#similar}

Related CPT2 variant pages (same residue, condition, or type): [CPT2 p.Ala643_Leu644insTer](/variant/cpt2-p-ala643-leu644inster), [CPT2 p.Arg382fs](/variant/cpt2-p-arg382fs), [CPT2 p.Asp576fs](/variant/cpt2-p-asp576fs), [CPT2 p.Gln33fs](/variant/cpt2-p-gln33fs), [CPT2 p.Glu285fs](/variant/cpt2-p-glu285fs), [CPT2 p.Leu556fs](/variant/cpt2-p-leu556fs), [CPT2 p.Leu575fs](/variant/cpt2-p-leu575fs), [CPT2 p.Leu592fs](/variant/cpt2-p-leu592fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2731936). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*