# NM_000098.3(CPT2):c.1581G>A (p.Glu527=)

https://sugi.bio/variant/cpt2-p-glu527

## Summary

**CPT2 p.Glu527= (c.1581G>A)** is classified **Likely benign** in CPT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-28). Absent from gnomAD v4.1; Associated with carnitine palmitoyltransferase II deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs2100274829 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CPT2 gene that is classified as likely benign — not considered disease-causing, 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.Glu527= |
| Coding change (HGVS c.) | c.1581G>A |
| MANE Select transcript | [NM_000098](https://www.ncbi.nlm.nih.gov/nuccore/NM_000098) |
| dbSNP | [rs2100274829](https://www.ncbi.nlm.nih.gov/snp/rs2100274829/) |
| Variant type | single nucleotide variant |
| Location | chr1:53211255-53211255 (GRCh38) |
| ClinVar | [VCV1643552](https://www.ncbi.nlm.nih.gov/clinvar/variation/1643552/) |

**All HGVS expressions:** `NC_000001.10:g.53676927G>A`, `NC_000001.11:g.53211255G>A`, `NG_008035.1:g.19827G>A`, `NM_000098.3:c.1581G>A`, `NM_001330589.2:c.1576+5G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.71) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.632, GERP -1, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.918**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.71**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.04**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-04-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-04-28 |

## 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 c.340+1G>C](/variant/cpt2-c-340-plus-1g-c), [CPT2 c.340+5G>A](/variant/cpt2-c-340-plus-5g-a), [CPT2 c.341-2A>G](/variant/cpt2-c-341-minus-2a-g), [CPT2 p.Ala67Gly](/variant/cpt2-p-ala67gly), [CPT2 p.Arg124Gln](/variant/cpt2-p-arg124gln), [CPT2 p.Arg124Ter](/variant/cpt2-p-arg124ter), [CPT2 p.Arg151Gln](/variant/cpt2-p-arg151gln), [CPT2 p.Arg151Trp](/variant/cpt2-p-arg151trp).

### 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 1643552). 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.*