# NM_000098.3(CPT2):c.451C>T (p.Arg151Trp)

https://sugi.bio/variant/cpt2-p-arg151trp

## Summary

**CPT2 p.Arg151Trp (c.451C>T)** is classified **Pathogenic** in CPT2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-03-05). AlphaMissense: likely pathogenic (0.6937); Very rare (popmax 0.005%, amr); Associated with CPT2-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs200080591 · 8 submitters · 6 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the CPT2 gene that is considered disease-causing, submitted by 8 submitters, and is linked to CPT2-related disorder.

*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.*

**Support & next steps:** [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.Arg151Trp |
| Coding change (HGVS c.) | c.451C>T |
| MANE Select transcript | [NM_000098](https://www.ncbi.nlm.nih.gov/nuccore/NM_000098) |
| dbSNP | [rs200080591](https://www.ncbi.nlm.nih.gov/snp/rs200080591/) |
| Variant type | single nucleotide variant |
| Location | chr1:53210125-53210125 (GRCh38) |
| ClinVar | [VCV1358726](https://www.ncbi.nlm.nih.gov/clinvar/variation/1358726/) |

**All HGVS expressions:** `NC_000001.10:g.53675797C>T`, `NC_000001.11:g.53210125C>T`, `NG_008035.1:g.18697C>T`, `NM_000098.3:c.451C>T`, `NM_001330589.2:c.451C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6937) — concordant with the pathogenic call
- REVEL 0.881 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.864 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 1.273, GERP -3.56, phastCons 0.592 — weakly conserved position
- CADD: **PHRED 22.7**. 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.*
- Regional missense constraint: **o/e 0.94** across the covering region of the MANE Select transcript (53,196,944–53,213,592), spanning 16,648 bp. Chi-square p 0.062. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/60,000 in the highest group · 30/1,614,014 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0219% | 4,573 |
| Admixed American (grpmax) | 0.005% | 20,000 |
| European (non-Finnish) | 0.0011% | 90,772 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **151** lies in a UniProt-annotated variant site (in cpt2d).

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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-05.

**Submitter consensus:** unanimous (8/8 Pathogenic).

**Submission history:** 8 submissions (2022–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-23 |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-11 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-21 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-21 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2026-03-05 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-15 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-09 |

## Associated conditions {#conditions}

[CPT2-related disorder](https://sugi.bio/atlas/disease/cpt2-related-disorder/), [carnitine palmitoyl transferase II deficiency, myopathic form](https://sugi.bio/atlas/disease/carnitine-palmitoyl-transferase-ii-deficiency-myopathic-form/), [carnitine palmitoyl transferase II deficiency, severe infantile form](https://sugi.bio/atlas/disease/carnitine-palmitoyl-transferase-ii-deficiency-severe-infantile-form/), [carnitine palmitoyl transferase II deficiency, neonatal form](https://sugi.bio/atlas/disease/carnitine-palmitoyl-transferase-ii-deficiency-neonatal-form/), [encephalopathy, acute, infection-induced, susceptibility to, 4](https://sugi.bio/atlas/disease/encephalopathy-acute-infection-induced-susceptibility-to-4/), [carnitine palmitoyltransferase II deficiency](https://sugi.bio/atlas/disease/carnitine-palmitoyltransferase-ii-deficiency/).

**Reported phenotype names (ClinVar):** CPT2-related disorder, Carnitine palmitoyltransferase II deficiency, Carnitine palmitoyl transferase II deficiency, severe infantile form, Encephalopathy, acute, infection-induced, susceptibility to, 4, Carnitine palmitoyl transferase II deficiency, myopathic form, Carnitine palmitoyl transferase II deficiency, neonatal form, CPT2-related condition, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, ANTENATAL, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, NEONATAL, CPT II DEFICIENCY, LETHAL NEONATAL.

## Same-residue context {#hotspot}

Residue **151** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CPT2 p.Arg151Gln](/variant/cpt2-p-arg151gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CPT2 variant pages (same residue, condition, or type): [CPT2 p.Arg151Gln](/variant/cpt2-p-arg151gln), [CPT2 p.Arg151=](/variant/cpt2-p-arg151), [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).

### 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 1358726). 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.*