Is ACADSB p.Phe265Leu (c.795C>G) pathogenic?

ACADSB p.Phe265Leu (c.795C>G) is classified Uncertain significance in ACADSB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). AlphaMissense: ambiguous (0.5624); Very rare (popmax 8.48e-05%, nfe); Associated with 2-methylbutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACADSB p.Phe265Leu (c.795C>G)?

ACADSB p.Phe265Leu (c.795C>G) is associated with 2-methylbutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADSB p.Phe265Leu (c.795C>G) in the general population?

ACADSB p.Phe265Leu (c.795C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is 2-methylbutyryl-CoA dehydrogenase deficiency inherited?

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

What do computational predictors say about ACADSB p.Phe265Leu (c.795C>G)?

AlphaMissense predicts ambiguous (score 0.5624) — an in-silico prediction, not a clinical call.

ACADSB p.Phe265Leu

c.795C>G · rs150619709 · VCV2166220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

2-methylbutyryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.5624	ambiguous
REVEL	0.64	indeterminate
SaProt	LLR -9.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.1	GERP -2.2, phastCons 0.84
Regional constraint	o/e 1.04	unconstrained · MANE · 45 kb · p 0.39 · regional, not allelic
Overall
CADD	14.91	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,792 alleles

Overall 0.000753% 11/1,461,522 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0141%	7,109
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)grpmax	8.48e-05%	1,179,792

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe265Leu
Coding: c.795C>G
MANE Select: NM_001609
dbSNP: rs150619709
Type: single nucleotide variant
Location: chr10:123043159 (GRCh38)
Gene constraint: LOEUF 0.891 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.47 · 1 PDB
Residue 265: a β-strand

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.Phe265= Conflicting classifications of pathogenicity ★ same residue
ACADSB c.1128+1G>A Likely pathogenic ★★ same condition
ACADSB c.1228+1G>A Likely pathogenic ★★ same condition
ACADSB c.303+3A>G Pathogenic/Likely pathogenic ★★ same condition
ACADSB p.Cys308Tyr Pathogenic/Likely pathogenic ★★ same condition
ACADSB p.Gln99Ter Pathogenic/Likely pathogenic ★★ same condition
ACADSB p.Glu387Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ACADSB p.Gly410Ser Pathogenic/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/acadsb-p-phe265leu (accessed [today's date]).

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