Is CPT2 p.Phe352Cys (c.1055T>G) pathogenic?

CPT2 p.Phe352Cys (c.1055T>G) is classified Benign/Likely benign in CPT2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.6441); Common (popmax 19.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with carnitine palmitoyltransferase II deficiency.

How is Carnitine palmitoyltransferase II deficiency inherited?

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

What do computational predictors say about CPT2 p.Phe352Cys (c.1055T>G)?

AlphaMissense predicts likely pathogenic (score 0.6441) — an in-silico prediction, not a clinical call.

CPT2 p.Phe352Cys

Q: What condition is associated with CPT2 p.Phe352Cys (c.1055T>G)?

CPT2 p.Phe352Cys (c.1055T>G) is associated with carnitine palmitoyltransferase II deficiency, carnitine palmitoyl transferase II deficiency, myopathic form, carnitine palmitoyl transferase II deficiency, severe infantile form (ClinVar).

Q: How common is CPT2 p.Phe352Cys (c.1055T>G) in the general population?

CPT2 p.Phe352Cys (c.1055T>G) is common (popmax 19.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1055T>G · rs2229291 · VCV92428

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.6441 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.6%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

carnitine palmitoyltransferase II deficiency

Computational evidence

Protein change
AlphaMissense	0.6441	likely pathogenic
REVEL	0.64	indeterminate
SaProt	LLR -10.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -1.2, phastCons 0.92
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	23.2	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 19.6% East Asian · 8,811/44,876 alleles

Filtering AF 19.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.2%

Overall 0.891% 14,389/1,614,208 alleles · common exomes 11,868/1,461,882 · genomes 2,521/152,326 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	19.6%	5
Admixed American	3.84%	26
African / African-American	2.11%	47
Remaining individualsnot grpmax-eligible	0.982%	102
Middle Eastern	0.874%	114
South Asian	0.539%	186
Ashkenazi Jewishnot grpmax-eligible	0.203%	493
European (non-Finnish)	0.0383%	2,611
Finnishnot grpmax-eligible	0.0219%	4,574

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.Phe352Cys
Coding: c.1055T>G
MANE Select: NM_000098
dbSNP: rs2229291
Type: single nucleotide variant
Location: chr1:53210729 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.52
Residue 352: a UniProt-annotated variant site (risk factor for iiae4; 3-fold decrease of affinity for l-carnitine; lower thermal stability compared to wild-type)

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

Disease context

carnitine palmitoyltransferase II deficiency — 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 encephalopathy, acute, infection-induced, susceptibility to, 4

For Carnitine palmitoyltransferase II deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

CPT2 p.Phe352Leu Uncertain significance ★ ⚠ same residue
CPT2 p.Phe352Ser Uncertain significance ★ ⚠ 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

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-phe352cys (accessed [today's date]).

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