# NM_001199753.2(CPT1C):c.879G>T (p.Pro293=)

https://sugi.bio/variant/cpt1c-p-pro293

## Summary

**CPT1C p.Pro293= (c.879G>T)** is classified **Uncertain significance** in CPT1C (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-30). Very rare (popmax 0.00167%, amr); Associated with hereditary spastic paraplegia 73.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1049933458 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CPT1C gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hereditary spastic paraplegia 73.

*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 dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | CPT1C is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Autosomal dominant spastic paraplegia type 73** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperreflexia — Very frequent (99-80%)
- Lower limb spasticity — Very frequent (99-80%)
- Spastic gait — Very frequent (99-80%)
- Degeneration of the lateral corticospinal tracts — Very frequent (99-80%)
- Babinski sign — Very frequent (99-80%)
- Progressive spastic paraplegia — Very frequent (99-80%)
- Urinary urgency — Frequent (79-30%)
- Urinary incontinence — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017763/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPT1C](https://sugi.bio/atlas/gene/CPT1C/) |
| Protein change (HGVS p.) | p.Pro293= |
| Coding change (HGVS c.) | c.879G>T |
| MANE Select transcript | [NM_001199753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001199753) |
| dbSNP | [rs1049933458](https://www.ncbi.nlm.nih.gov/snp/rs1049933458/) |
| Variant type | single nucleotide variant |
| Location | chr19:49705114-49705114 (GRCh38) |
| ClinVar | [VCV852559](https://www.ncbi.nlm.nih.gov/clinvar/variation/852559/) |

**All HGVS expressions:** `NC_000019.10:g.49705114G>T`, `NC_000019.9:g.50208371G>T`, `NG_050570.1:g.19237G>T`, `NM_001136052.3:c.846G>T`, `NM_001199752.3:c.879G>T`, `NM_001199753.2:c.879G>T`, `NM_001378482.1:c.846G>T`, `NM_001378483.1:c.879G>T`, `NM_001378484.1:c.879G>T`, `NM_001378485.1:c.846G>T`, `NM_001378486.1:c.879G>T`, `NM_001378487.1:c.846G>T`, `NM_001378488.1:c.879G>T`, `NM_152359.3:c.879G>T`, `NR_108072.2:n.1349G>T`

## 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 -2.844 — fast-evolving / accelerated position
- CADD: **PHRED 13.85**. 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 (G>C, Δ0.23 donor loss), 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.*
- Pangolin: Δ**0.26** (loss), gain 0.02 / loss 0.26. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,990 in the highest group · 2/1,613,896 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,990 |
| African / African-American | 0.00134% | 74,896 |

*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}

**CPT1C** population constraint: LOEUF 0.778, pLI 2.8029e-12, missense-Z 1.1543. *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):

- **hereditary spastic paraplegia** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.81, 73% of residues very-high.

**1 experimental structure(s)** (PDB): [2M76](https://www.rcsb.org/structure/2M76).

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

*Describes the biological roles of CPT1C (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:** CPT1C's established molecular role includes palmitoyl-(protein) hydrolase activity.


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

**Molecular function:** palmitoyl-(protein) hydrolase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-05-30.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-05-30 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 73](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-73/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 73, Spastic paraplegia 73, autosomal dominant.

## Similar variants {#similar}

Related CPT1C variant pages (same residue, condition, or type): [CPT1C p.Pro293Arg](/variant/cpt1c-p-pro293arg), [CPT1C p.Pro293Leu](/variant/cpt1c-p-pro293leu), [CPT1C c.1160+3A>G](/variant/cpt1c-c-1160-plus-3a-g), [CPT1C p.Ala117Val](/variant/cpt1c-p-ala117val), [CPT1C p.Ala19Thr](/variant/cpt1c-p-ala19thr), [CPT1C p.Ala203Thr](/variant/cpt1c-p-ala203thr), [CPT1C p.Ala401Val](/variant/cpt1c-p-ala401val), [CPT1C p.Ala422Thr](/variant/cpt1c-p-ala422thr).

### 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 852559). 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.*