# NM_000098.3(CPT2):c.631C>T (p.Pro211Ser)

https://sugi.bio/variant/cpt2-p-pro211ser

## Summary

**CPT2 p.Pro211Ser (c.631C>T)** is classified **Conflicting classifications of pathogenicity** in CPT2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-22). AlphaMissense: likely pathogenic (0.9378); Very rare (popmax 0.0011%, sas); Associated with carnitine palmitoyl transferase II deficiency, neonatal form.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs796051942 · 3 submitters · 4 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CPT2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to carnitine palmitoyl transferase II deficiency, neonatal 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/0017151/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.Pro211Ser |
| Coding change (HGVS c.) | c.631C>T |
| MANE Select transcript | [NM_000098](https://www.ncbi.nlm.nih.gov/nuccore/NM_000098) |
| dbSNP | [rs796051942](https://www.ncbi.nlm.nih.gov/snp/rs796051942/) |
| Variant type | single nucleotide variant |
| Location | chr1:53210305-53210305 (GRCh38) |
| ClinVar | [VCV2688862](https://www.ncbi.nlm.nih.gov/clinvar/variation/2688862/) |

**All HGVS expressions:** `NC_000001.10:g.53675977C>T`, `NC_000001.11:g.53210305C>T`, `NG_008035.1:g.18877C>T`, `NM_000098.3:c.631C>T`, `NM_001330589.2:c.631C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9378)
- REVEL 0.91 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.634 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.716, GERP 2.23, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.5**. 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 **0.0011%** (sas) · 1/91,086 in the highest group · 2/1,614,170 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |
| South Asian (grpmax) | 0.0011% | 91,086 |

Remaining individuals 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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-02-22.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-22 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-23 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-02 |

## Associated conditions {#conditions}

[carnitine palmitoyl transferase II deficiency, neonatal form](https://sugi.bio/atlas/disease/carnitine-palmitoyl-transferase-ii-deficiency-neonatal-form/), [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/), [encephalopathy, acute, infection-induced, susceptibility to, 4](https://sugi.bio/atlas/disease/encephalopathy-acute-infection-induced-susceptibility-to-4/).

**Reported phenotype names (ClinVar):** Carnitine palmitoyl transferase II deficiency, neonatal form, not provided, Carnitine palmitoyl transferase II deficiency, myopathic form, Carnitine palmitoyl transferase II deficiency, severe infantile form, Encephalopathy, acute, infection-induced, susceptibility to, 4, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, ANTENATAL, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, NEONATAL, CPT II DEFICIENCY, LETHAL NEONATAL, CPT2 DEFICIENCY, LETHAL NEONATAL, Carnitine palmitoyltransferase II deficiency, lethal neonatal.

## Same-residue context {#hotspot}

Residue **211** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CPT2 p.Pro211fs](/variant/cpt2-p-pro211fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CPT2 variant pages (same residue, condition, or type): [CPT2 p.Pro211fs](/variant/cpt2-p-pro211fs), [CPT2 p.Pro211Leu](/variant/cpt2-p-pro211leu), [CPT2 p.Pro211=](/variant/cpt2-p-pro211), [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 2026-10-14); 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 2026-10-14); 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 2688862). 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.*