ClinGen expert panel — ACADVL VCEP
Benign for very long chain acyl-CoA dehydrogenase deficiency. Applied ACMG criteria (verbatim):
BP7 BP4 BA1
Curation rationale (ClinGen, verbatim)
The c.1038G>A variant in ACADVL is a synonymous variant which occurs in exon 10. The highest population minor allele frequency in gnomAD v2.1.1 is 0.08089 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from 2 in silico splicing predictors (SpliceAI, MutationTaster) support that this variant does not affect splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the 100 vertebrate Basewise Conservation by PhyloP track in the UCSC genome browser (BP4, BP7). In summary, this variant meets the criteria to be classified as 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: BA1, BP4, BP7 (VCEP specifications v2.0, approved on 09/16/2021).
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 -4 | GERP -3.7 |
| Overall | ||
| CADD | 0.3 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 8.14% | 12 |
| Admixed American | 0.66% | 152 |
| Remaining individualsnot grpmax-eligible | 0.54% | 185 |
| Middle Eastern | 0.433% | 231 |
| European (non-Finnish) | 0.0219% | 4,556 |
| South Asian | 0.0154% | 6,502 |
| East Asian | 0.00223% | 44,880 |
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.Ala346=
- Coding
- c.1038G>A
- MANE Select
- NM_000018
- dbSNP
- rs8064573
- Type
- single nucleotide variant
- Location
- chr17:7222826 (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 346
- an α-helix; the 'catalytic' region
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.Ala346Glu Uncertain significance ★ ⚠ same residue
- ACADVL p.Ala346Gly Uncertain significance ★ ⚠ same residue
- ACADVL p.Ala346Val Uncertain significance ★ ⚠ 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
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-ala346 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown