Is ACADVL p.Pro35fs (c.104del) pathogenic?

ACADVL p.Pro35fs (c.104del) is classified Pathogenic in ACADVL (ClinVar, Expert panel, 4 submitters; last evaluated 2022-04-06). Very rare (popmax 0.00392%, amr); Associated with very long chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADVL p.Pro35fs (c.104del)?

ACADVL p.Pro35fs (c.104del) is associated with very long chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADVL p.Pro35fs (c.104del) in the general population?

ACADVL p.Pro35fs (c.104del) is very rare (popmax 0.00392%, amr) (gnomAD).

ACADVL p.Pro35fs

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.104del · rs1443151475 · VCV541718

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00392%, amr)

Conditions

very long chain acyl-CoA dehydrogenase deficiency

ClinGen expert panel — ACADVL VCEP

Pathogenic for very long chain acyl-CoA dehydrogenase deficiency. Applied ACMG criteria (verbatim):

PVS1 PP4_Moderate PM2_Supporting PM3

Curation rationale (ClinGen, verbatim)

The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID: 25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021).

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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP -2.7, phastCons 0.001
Overall
CADD	18.74	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00392% Admixed American · 2/50,974 alleles

Filtering AF 0.000651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000243%

Overall 0.000454% 7/1,540,236 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00392%	25,487
European (non-Finnish)	0.000435%	229,885

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.Pro35fs
Coding: c.104del
MANE Select: NM_000018
dbSNP: rs1443151475
Type: Deletion
Location: chr17:7220161 (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 35: the 'disordered' 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

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ACADVL p.Ala347fs Likely pathogenic ★★★ same condition
ACADVL p.Ala544fs Likely pathogenic ★★★ same condition
ACADVL p.Ala577fs Likely pathogenic ★★★ same condition
ACADVL p.Arg512fs Likely pathogenic ★★★ same condition
ACADVL p.Asp257fs 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-pro35fs (accessed [today's date]).

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