Is CPT1C p.Ser549Phe (c.1646C>T) pathogenic?

CPT1C p.Ser549Phe (c.1646C>T) is classified Uncertain significance in CPT1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely benign (0.1687); Very rare (popmax 0.000932%, nfe); Associated with hereditary spastic paraplegia 73.

What condition is associated with CPT1C p.Ser549Phe (c.1646C>T)?

CPT1C p.Ser549Phe (c.1646C>T) is associated with hereditary spastic paraplegia 73 (ClinVar).

How common is CPT1C p.Ser549Phe (c.1646C>T) in the general population?

CPT1C p.Ser549Phe (c.1646C>T) is very rare (popmax 0.000932%, nfe) (gnomAD).

How is Autosomal dominant spastic paraplegia type 73 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CPT1C p.Ser549Phe (c.1646C>T)?

AlphaMissense predicts likely benign (score 0.1687) — an in-silico prediction, not a clinical call.

CPT1C p.Ser549Phe

c.1646C>T · VCV3720632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 73

Computational evidence

Protein change
AlphaMissense	0.1687	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	phastCons 0.77
Regional constraint	o/e 0.87	unconstrained · MANE · 4,824 bp · p 0.0093 · regional, not allelic
Overall
CADD	18.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,180,044 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000752% 11/1,461,888 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CPT1C
Protein: p.Ser549Phe
Coding: c.1646C>T
MANE Select: NM_001199753
Type: single nucleotide variant
Location: chr19:49710399 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.81 · 1 PDB

Full CPT1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 73 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant spastic paraplegia type 73 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CPT1C p.Ser549= Likely benign ★★ same residue
CPT1C c.1160+3A>G Uncertain significance ★★ same condition
CPT1C p.Ala117Val Uncertain significance ★★ ⚠ same condition
CPT1C p.Ala19Thr Uncertain significance ★★ ⚠ same condition
CPT1C p.Ala203Thr Uncertain significance ★★ ⚠ same condition
CPT1C p.Ala401Val Uncertain significance ★★ ⚠ same condition
CPT1C p.Ala422Thr Uncertain significance ★★ ⚠ same condition
CPT1C p.Ala431Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cpt1c-p-ser549phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown