ACADVL p.Ser221=
c.663C>T · rs144255994 · VCV383052
ClinGen expert panel — ACADVL VCEP
Likely Benign for very long chain acyl-CoA dehydrogenase deficiency. Applied ACMG criteria (verbatim):
BS1 BP7 BP4
Curation rationale (ClinGen, verbatim)
The NM_000018.4(ACADVL):c.663C>T (p.Ser221=) variant is a synonymous (silent) variant that is not predicted by SpliceAI, MaxEntScn and NNSplice to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00353 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, BP4, BP7.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.94 | GERP -0.85, phastCons 0.006 |
| Overall | ||
| CADD | 10.93 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.347% | 288 |
| Admixed American | 0.0616% | 1,622 |
| Remaining individualsnot grpmax-eligible | 0.0368% | 2,718 |
| Middle Eastern | 0.033% | 3,031 |
| European (non-Finnish) | 0.00415% | 24,082 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,606 |
| South Asian | 0.0011% | 91,082 |
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
- ACADVL
- Protein
- p.Ser221=
- Coding
- c.663C>T
- MANE Select
- NM_000018
- dbSNP
- rs144255994
- Type
- single nucleotide variant
- Location
- chr17:7221992 (GRCh38)
- Gene constraint
- LOEUF 1.077 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 90.65 · 3 PDB
- Residue 221
- a β-strand; the 'catalytic' region; a binding site
Disease context
very long chain acyl-CoA dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Very long chain acyl-CoA dehydrogenase deficiency (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- ACADVL p.Ser221Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
- ACADVL c.1077+1G>A Likely pathogenic ★★★ same condition
- ACADVL c.1077+1G>T Likely pathogenic ★★★ same condition
- ACADVL c.1077+2T>A Pathogenic ★★★ same condition
- ACADVL c.1077+2T>C Pathogenic ★★★ same condition
- ACADVL c.1182+1G>A Likely pathogenic ★★★ same condition
- ACADVL c.1269+1G>A Likely pathogenic ★★★ same condition
- ACADVL c.1532+1G>A 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/acadvl-p-ser221 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown