# NM_001876.4(CPT1A):c.1662T>C (p.Phe554=)

https://sugi.bio/variant/cpt1a-p-phe554

## Summary

**CPT1A p.Phe554= (c.1662T>C)** is classified **Likely benign** in CPT1A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-03). Very rare (popmax 0.00223%, eas); Associated with carnitine palmitoyl transferase 1A deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs1855048075 · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CPT1A gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to carnitine palmitoyl transferase 1A 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) | Infancy, Neonatal |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CPT1A is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Carnitine palmitoyl transferase 1A deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Atypical behavior — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Reduced tendon reflexes — Very frequent (99-80%)
- Hepatic failure — Very frequent (99-80%)
- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Hypoglycemia — Very frequent (99-80%)
- Abnormality of speech or vocalization — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001120/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPT1A](https://sugi.bio/atlas/gene/CPT1A/) |
| Protein change (HGVS p.) | p.Phe554= |
| Coding change (HGVS c.) | c.1662T>C |
| MANE Select transcript | [NM_001876](https://www.ncbi.nlm.nih.gov/nuccore/NM_001876) |
| dbSNP | [rs1855048075](https://www.ncbi.nlm.nih.gov/snp/rs1855048075/) |
| Variant type | single nucleotide variant |
| Location | chr11:68773343-68773343 (GRCh38) |
| ClinVar | [VCV1099829](https://www.ncbi.nlm.nih.gov/clinvar/variation/1099829/) |

**All HGVS expressions:** `NC_000011.10:g.68773343A>G`, `NC_000011.9:g.68540811A>G`, `NG_011801.1:g.73589T>C`, `NM_001031847.3:c.1662T>C`, `NM_001876.4:c.1662T>C`

## 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 -1.477, GERP -4.14 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.035**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.27 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,882 in the highest group · 1/1,614,166 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}

**CPT1A** population constraint: LOEUF 0.709, pLI 2.7892e-09, missense-Z 3.0969; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 palmitoyl transferase 1A deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.55, 80% of residues very-high.

**1 experimental structure(s)** (PDB): [2LE3](https://www.rcsb.org/structure/2LE3).

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

*Describes the biological roles of CPT1A (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:** CPT1A's established molecular role includes carnitine O-palmitoyltransferase activity.


### Pathways affected {#pathways}

CPT1A participates in **3 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) | electronic |
| [RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression](https://reactome.org/content/detail/R-HSA-9933387) | electronic |

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

**Molecular function:** carnitine O-palmitoyltransferase activity, protein-macromolecule adaptor activity.

**Biological process:** long-chain fatty acid metabolic process, carnitine metabolic process, epithelial cell differentiation, positive regulation of innate immune response.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-12-03.

**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 | 2019-12-03 |

## Associated conditions {#conditions}

[carnitine palmitoyl transferase 1A deficiency](https://sugi.bio/atlas/disease/carnitine-palmitoyl-transferase-1a-deficiency/).

**Reported phenotype names (ClinVar):** Carnitine palmitoyl transferase 1A deficiency, Carnitine palmitoyltransferase 1A deficiency, Carnitine palmitoyltransferase type I deficiency, CPT deficiency, hepatic, type IA, CPT I DEFICIENCY, CPT DEFICIENCY, HEPATIC, TYPE I.

## Same-residue context {#hotspot}

Residue **554** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CPT1A p.Phe554fs](/variant/cpt1a-p-phe554fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CPT1A variant pages (same residue, condition, or type): [CPT1A p.Phe554fs](/variant/cpt1a-p-phe554fs), [CPT1A c.1163+1G>A](/variant/cpt1a-c-1163-plus-1g-a), [CPT1A c.1163+2T>C](/variant/cpt1a-c-1163-plus-2t-c), [CPT1A c.1352+1G>C](/variant/cpt1a-c-1352-plus-1g-c), [CPT1A c.1459-1G>A](/variant/cpt1a-c-1459-minus-1g-a), [CPT1A c.1575+1G>T](/variant/cpt1a-c-1575-plus-1g-t), [CPT1A c.2028+2T>G](/variant/cpt1a-c-2028-plus-2t-g), [CPT1A c.281+1G>A](/variant/cpt1a-c-281-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1099829). 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.*