Is CPT1C p.Ala381Val (c.1142C>T) pathogenic?

CPT1C p.Ala381Val (c.1142C>T) is classified Uncertain significance in CPT1C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: likely benign (0.2959); Very rare (popmax 0.000933%, nfe); Associated with hereditary spastic paraplegia 73.

What condition is associated with CPT1C p.Ala381Val (c.1142C>T)?

CPT1C p.Ala381Val (c.1142C>T) is associated with hereditary spastic paraplegia 73 (ClinVar).

How common is CPT1C p.Ala381Val (c.1142C>T) in the general population?

CPT1C p.Ala381Val (c.1142C>T) is very rare (popmax 0.000933%, 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.Ala381Val (c.1142C>T)?

AlphaMissense predicts likely benign (score 0.2959) — an in-silico prediction, not a clinical call.

CPT1C p.Ala381Val

c.1142C>T · rs1436873820 · VCV657869

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 73

Computational evidence

Protein change
AlphaMissense	0.2959	likely benign
REVEL	0.728	pathogenic-leaning
SaProt	LLR -8.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.77 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,179,600 alleles

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

Overall 0.000806% 13/1,613,308 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,460
Finnishnot grpmax-eligible	0.00156%	63,936
European (non-Finnish)grpmax	0.000933%	107,236

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Ala381Val
Coding: c.1142C>T
MANE Select: NM_001199753
dbSNP: rs1436873820
Type: single nucleotide variant
Location: chr19:49706086 (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 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
CPT1C p.Ala4Glu 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-ala381val (accessed [today's date]).

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