Is CPT2 p.Ser655Tyr (c.1964C>A) pathogenic?

CPT2 p.Ser655Tyr (c.1964C>A) is classified Conflicting classifications of pathogenicity in CPT2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-05-06). AlphaMissense: likely benign (0.0814); Ultra-rare (popmax 0.0178%, mid); Associated with Inborn genetic diseases.

How common is CPT2 p.Ser655Tyr (c.1964C>A) in the general population?

CPT2 p.Ser655Tyr (c.1964C>A) is ultra-rare (popmax 0.0178%, mid) (gnomAD).

What do computational predictors say about CPT2 p.Ser655Tyr (c.1964C>A)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

CPT2 p.Ser655Tyr

Q: What condition is associated with CPT2 p.Ser655Tyr (c.1964C>A)?

CPT2 p.Ser655Tyr (c.1964C>A) is associated with Inborn genetic diseases, carnitine palmitoyl transferase II deficiency, myopathic form, carnitine palmitoyl transferase II deficiency, severe infantile form (ClinVar).

c.1964C>A · rs373714948 · VCV203658

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.4, phastCons 0.06
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.062 · regional, not allelic
Overall
CADD	18.44	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 0.0178% Middle Eastern · 1/5,624 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00149% 24/1,613,312 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0178%	5,624
Admixed American	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.00801%	12,486
African / African-American	0.00133%	74,912
European (non-Finnish)	0.00102%	98,325

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.Ser655Tyr
Coding: c.1964C>A
MANE Select: NM_000098
dbSNP: rs373714948
Type: single nucleotide variant
Location: chr1:53213582 (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

Inborn genetic diseases — 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 carnitine palmitoyltransferase II deficiency

Similar variants

CPT2 p.Ser655Pro Uncertain significance ★ ⚠ same residue
CPT2 p.Ser655= Likely benign ★ 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-ser655tyr (accessed [today's date]).

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