Is ACADVL p.Phe421fs (c.1262_1263del) pathogenic?

ACADVL p.Phe421fs (c.12621263del) is classified Pathogenic in ACADVL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). Associated with very long chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADVL p.Phe421fs (c.1262_1263del)?

ACADVL p.Phe421fs (c.1262_1263del) is associated with very long chain acyl-CoA dehydrogenase deficiency (ClinVar).

ACADVL p.Phe421fs

Q: How is Very long chain acyl-CoA dehydrogenase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1262_1263del · VCV4081618

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

very long chain acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 2.1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: ACADVL
Protein: p.Phe421fs
Coding: c.1262_1263del
MANE Select: NM_000018
Type: Deletion
Location: chr17:7223722 (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 421: an α-helix; the 'catalytic' region

Full ACADVL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

very long chain acyl-CoA dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Very long chain acyl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ACADVL p.Phe421Ser Uncertain significance ★ ⚠ same residue
ACADVL p.Phe421= Likely benign ★ same residue
ACADVL c.1606-3_1606-2del Pathogenic ★★★ same condition
ACADVL c.1752-3_1755del Pathogenic ★★★ same condition
ACADVL c.343del Pathogenic ★★★ same condition
ACADVL p.Ala347fs Likely pathogenic ★★★ same condition
ACADVL p.Ala544fs Likely pathogenic ★★★ same condition
ACADVL p.Ala577fs 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-phe421fs (accessed [today's date]).

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