Is CPT2 p.Lys537fs (c.1608dup) pathogenic?

CPT2 p.Lys537fs (c.1608dup) is classified Pathogenic/Likely pathogenic in CPT2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-31). Very rare (popmax 0.00134%, afr); Associated with encephalopathy, acute, infection-induced, susceptibility to, 4.

What condition is associated with CPT2 p.Lys537fs (c.1608dup)?

CPT2 p.Lys537fs (c.1608dup) 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.Lys537fs (c.1608dup) in the general population?

CPT2 p.Lys537fs (c.1608dup) is very rare (popmax 0.00134%, afr) (gnomAD).

CPT2 p.Lys537fs

c.1608dup · rs1553169813 · VCV553793

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (4 of 5, 39 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 2.1, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,834 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,611,058 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,380
African / African-Americangrpmax	0.00134%	74,834
European (non-Finnish)	0.000339%	294,676

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: CPT2
Protein: p.Lys537fs
Coding: c.1608dup
MANE Select: NM_000098
dbSNP: rs1553169813
Type: Duplication
Location: chr1:53211280 (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.Lys537Glu Uncertain significance ★ ⚠ same residue
CPT2 p.Lys537= Likely benign ★ same residue
CPT2 p.Arg303fs Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.Asn349fs Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.Asp279fs Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.His242fs Likely pathogenic ★★ same condition
CPT2 p.Pro211fs Pathogenic/Likely pathogenic ★★ same condition
CPT2 p.Thr442fs 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-lys537fs (accessed [today's date]).

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