# NM_000098.3(CPT2):c.241_242del (p.Glu81fs)

https://sugi.bio/variant/cpt2-p-glu81fs

## Summary

**CPT2 p.Glu81fs (c.241_242del)** is classified **Likely pathogenic** in CPT2 (ClinVar, No assertion criteria, 1 submitter). Very rare (popmax 0.0011%, sas); Associated with carnitine palmitoyl transferase II deficiency, severe infantile form.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs1645358577 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CPT2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to carnitine palmitoyl transferase II deficiency, severe infantile form.

*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 |
| 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/0017150/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.Glu81fs |
| Coding change (HGVS c.) | c.241_242del |
| MANE Select transcript | [NM_000098](https://www.ncbi.nlm.nih.gov/nuccore/NM_000098) |
| dbSNP | [rs1645358577](https://www.ncbi.nlm.nih.gov/snp/rs1645358577/) |
| Variant type | Deletion |
| Location | chr1:53202329-53202330 (GRCh38) |
| ClinVar | [VCV917934](https://www.ncbi.nlm.nih.gov/clinvar/variation/917934/) |

**All HGVS expressions:** `NC_000001.10:g.53668002_53668003del`, `NC_000001.11:g.53202330_53202331del`, `NG_008035.1:g.10902_10903del`, `NM_000098.3:c.241_242del`, `NM_000098.3:c.241_242delGA`, `NM_001330589.2:c.241_242del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.576, GERP 2.42, phastCons 1 — highly conserved position (PP3-type support)
- 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 3 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 **0.0011%** (sas) · 1/91,044 in the highest group · 1/1,460,720 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | no assertion criteria provided | research |  |

## Associated conditions {#conditions}

[carnitine palmitoyl transferase II deficiency, severe infantile form](https://sugi.bio/atlas/disease/carnitine-palmitoyl-transferase-ii-deficiency-severe-infantile-form/).

**Reported phenotype names (ClinVar):** Carnitine palmitoyl transferase II deficiency, severe infantile form, CPT II deficiency, infantile, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY WITH HYPOKETOTIC HYPOGLYCEMIA, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, HEPATOCARDIOMUSCULAR, CPT II DEFICIENCY, HEPATIC, CPT2 DEFICIENCY, INFANTILE.

## Similar variants {#similar}

Related CPT2 variant pages (same residue, condition, or type): [CPT2 p.Ala643_Leu644insTer](/variant/cpt2-p-ala643-leu644inster), [CPT2 p.Gln33fs](/variant/cpt2-p-gln33fs), [CPT2 p.Glu285fs](/variant/cpt2-p-glu285fs), [CPT2 p.Leu556fs](/variant/cpt2-p-leu556fs), [CPT2 p.Leu592fs](/variant/cpt2-p-leu592fs), [CPT2 p.Lys414fs](/variant/cpt2-p-lys414fs), [CPT2 p.Phe516fs](/variant/cpt2-p-phe516fs), [CPT2 p.Phe602fs](/variant/cpt2-p-phe602fs).

### 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 917934). 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.*