Is CPT2 p.Val466Ala (c.1397T>C) pathogenic?

CPT2 p.Val466Ala (c.1397T>C) is classified Uncertain significance in CPT2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.2654); Very rare (popmax 0.00907%, nfe); Associated with encephalopathy, acute, infection-induced, susceptibility to, 4.

What condition is associated with CPT2 p.Val466Ala (c.1397T>C)?

CPT2 p.Val466Ala (c.1397T>C) is associated with encephalopathy, acute, infection-induced, susceptibility to, 4, carnitine palmitoyl transferase II deficiency, myopathic form, carnitine palmitoyl transferase II deficiency, severe infantile form (ClinVar).

How common is CPT2 p.Val466Ala (c.1397T>C) in the general population?

CPT2 p.Val466Ala (c.1397T>C) is very rare (popmax 0.00907%, nfe) (gnomAD).

What do computational predictors say about CPT2 p.Val466Ala (c.1397T>C)?

AlphaMissense predicts likely benign (score 0.2654) — an in-silico prediction, not a clinical call.

CPT2 p.Val466Ala

c.1397T>C · rs200399018 · VCV569723

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00907%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

encephalopathy, acute, infection-induced, susceptibility to, 4

Computational evidence

Protein change
AlphaMissense	0.2654	likely benign
REVEL	0.77	pathogenic-leaning
SaProt	LLR -8.96	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	25.3	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 0.00907% European (non-Finnish) · 107/1,180,032 alleles

Filtering AF 0.00766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00708%

Overall 0.00688% 111/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00907%	11,028
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00223%	44,890

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: CPT2
Protein: p.Val466Ala
Coding: c.1397T>C
MANE Select: NM_000098
dbSNP: rs200399018
Type: single nucleotide variant
Location: chr1:53211071 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.52

Full CPT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

encephalopathy, acute, infection-induced, susceptibility to, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: carnitine palmitoyl transferase II deficiency, myopathic form carnitine palmitoyl transferase II deficiency, severe infantile form carnitine palmitoyl transferase II deficiency, neonatal form carnitine palmitoyltransferase II deficiency

Similar variants

CPT2 p.Val466fs Likely pathogenic ★★ same residue
CPT2 c.340+1G>C Pathogenic/Likely pathogenic ★★ same condition
CPT2 c.340+5G>A Likely pathogenic ★★ same condition
CPT2 c.341-2A>G Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.Ala67Gly Likely pathogenic ★★ ⚠ same condition
CPT2 p.Arg124Gln Likely pathogenic ★★ ⚠ same condition
CPT2 p.Arg124Ter Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.Arg151Gln Pathogenic/Likely pathogenic ★★ ⚠ 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/cpt2-p-val466ala (accessed [today's date]).

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