ACADVL p.Phe142Ser
c.425T>C · rs398123088 · VCV92283
ClinGen expert panel — ACADVL VCEP
Uncertain Significance for very long chain acyl-CoA dehydrogenase deficiency. Applied ACMG criteria (verbatim):
PM3_Supporting PM2_Supporting PP3 PP4
Curation rationale (ClinGen, verbatim)
The c.425T>C variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 142 (p.Phe142Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94, which is above the threshold 0.75, evidence that correlates with impact to ACADVL function (PP3). At least one patient with this variant displayed organic acidemia and fatty acid oxidation issues, which are highly specific for VLCAD deficiency (PP4, PMID: 27629047, PMID: 28980192). This individual was also reported homozygous for the variant (PMID: 27629047; points=0.5; PM3_supporting). In summary, this variant meets the criteria to be classified as VUS 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: PM2,PM3_supporting PP3, PP4
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8408 | likely pathogenic |
|---|---|---|
| REVEL | 0.944 | strongly pathogenic-leaning |
| SaProt | LLR -12.91 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 1.02 | unconstrained · MANE · 5,109 bp · p 0.51 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- ACADVL
- Protein
- p.Phe142Ser
- Coding
- c.425T>C
- MANE Select
- NM_000018
- dbSNP
- rs398123088
- Type
- single nucleotide variant
- Location
- chr17:7221006 (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 142
- the 'catalytic' region; a turn
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 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
- ACADVL c.1532+2T>C 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-phe142ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown