Is CPT2 p.Ile253Val (c.757A>G) pathogenic?

CPT2 p.Ile253Val (c.757A>G) is classified Uncertain significance in CPT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-25). AlphaMissense: likely benign (0.0532); Very rare (popmax 0.00167%, amr).

How common is CPT2 p.Ile253Val (c.757A>G) in the general population?

CPT2 p.Ile253Val (c.757A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CPT2 p.Ile253Val (c.757A>G)?

AlphaMissense predicts likely benign (score 0.0532) — an in-silico prediction, not a clinical call.

CPT2 p.Ile253Val

c.757A>G · rs914465235 · VCV447220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0532	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -6.68	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 0.22	GERP -3.3, phastCons 0.12
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	5.448	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 0.00167% Admixed American · 1/60,004 alleles

Overall 0.000124% 2/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	8.47e-05%	1,180,048

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.Ile253Val
Coding: c.757A>G
MANE Select: NM_000098
dbSNP: rs914465235
Type: single nucleotide variant
Location: chr1:53210431 (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

Similar variants

CPT2 p.Ile253= Likely benign ★ same residue
CPT2 c.340+1G>C Pathogenic/Likely pathogenic ★★ same type
CPT2 c.340+5G>A Likely pathogenic ★★ same type
CPT2 c.341-2A>G Pathogenic/Likely pathogenic ★★ same type
CPT2 p.Ala67Gly Likely pathogenic ★★ ⚠ same type
CPT2 p.Arg124Gln Likely pathogenic ★★ ⚠ same type
CPT2 p.Arg124Ter Pathogenic/Likely pathogenic ★★ same type
CPT2 p.Arg151Gln Pathogenic/Likely pathogenic ★★ ⚠ same type

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-ile253val (accessed [today's date]).

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