Is ACADSB p.Val219Met (c.655G>A) pathogenic?

ACADSB p.Val219Met (c.655G>A) is classified Conflicting classifications of pathogenicity in ACADSB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-04). AlphaMissense: ambiguous (0.4262); Ultra-rare (popmax 0.0668%, eas); Associated with 2-methylbutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACADSB p.Val219Met (c.655G>A)?

ACADSB p.Val219Met (c.655G>A) is associated with 2-methylbutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADSB p.Val219Met (c.655G>A) in the general population?

ACADSB p.Val219Met (c.655G>A) is ultra-rare (popmax 0.0668%, eas) (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.Val219Met (c.655G>A)?

AlphaMissense predicts ambiguous (score 0.4262) — an in-silico prediction, not a clinical call.

ACADSB p.Val219Met

c.655G>A · rs553730391 · VCV577108

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4262 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

2-methylbutyryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.4262	ambiguous
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -14.32	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 45 kb · p 0.39 · regional, not allelic
Overall
CADD	27.4	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 0.0668% East Asian · 30/44,878 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00254% 41/1,614,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0668%	1,496
South Asian	0.00769%	13,012
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000254%	393,342

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.Val219Met
Coding: c.655G>A
MANE Select: NM_001609
dbSNP: rs553730391
Type: single nucleotide variant
Location: chr10:123041353 (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 219: 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.Val219fs Pathogenic/Likely pathogenic ★★ 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-val219met (accessed [today's date]).

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