Is ACADSB p.Leu23fs (c.68dup) pathogenic?

ACADSB p.Leu23fs (c.68dup) is classified Likely pathogenic in ACADSB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). Very rare (popmax 0.00133%, afr); Associated with 2-methylbutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACADSB p.Leu23fs (c.68dup)?

ACADSB p.Leu23fs (c.68dup) is associated with 2-methylbutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADSB p.Leu23fs (c.68dup) in the general population?

ACADSB p.Leu23fs (c.68dup) is very rare (popmax 0.00133%, afr) (gnomAD).

How is 2-methylbutyryl-CoA dehydrogenase deficiency inherited?

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

ACADSB p.Leu23fs

c.68dup · rs1850369146 · VCV3075976

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

2-methylbutyryl-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 2 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.3	GERP 0.5, phastCons 1
Overall
CADD	24.3	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 0.00133% African / African-American · 1/74,918 alleles

Overall 0.000657% 1/152,152 alleles · very rare

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: ACADSB
Protein: p.Leu23fs
Coding: c.68dup
MANE Select: NM_001609
dbSNP: rs1850369146
Type: Duplication
Location: chr10:123034378 (GRCh38)
Gene constraint: LOEUF 0.891 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.47 · 1 PDB

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

Disease context

2-methylbutyryl-CoA dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 2-methylbutyryl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACADSB p.Leu23Val Uncertain significance ★ ⚠ same residue
ACADSB p.Glu126fs Pathogenic/Likely pathogenic ★★ same condition
ACADSB p.Val219fs Pathogenic/Likely pathogenic ★★ same condition
ACADSB c.1128+25_1128+26dup Benign/Likely benign ★★ same condition
ACADSB p.Arg7fs Likely pathogenic ★ same condition
ACADSB p.Gly293_Arg294insTer Pathogenic ★ same condition
ACADSB c.1128+2dup Uncertain significance ★ same condition
ACADSB c.1128+20_1128+26dup Likely benign ★ 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/acadsb-p-leu23fs (accessed [today's date]).

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