Is ACADSB p.His338= (c.1014C>T) pathogenic?

ACADSB p.His338= (c.1014C>T) is classified Benign in ACADSB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-13). Rare (popmax 0.401%, afr); Associated with 2-methylbutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACADSB p.His338= (c.1014C>T)?

ACADSB p.His338= (c.1014C>T) is associated with 2-methylbutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADSB p.His338= (c.1014C>T) in the general population?

ACADSB p.His338= (c.1014C>T) is rare (popmax 0.401%, 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.His338=

c.1014C>T · rs57339164 · VCV536348

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.401%, afr)

Conditions

2-methylbutyryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.9
Overall
CADD	0.291	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.401% African / African-American · 300/74,866 alleles

Filtering AF 0.363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.349%

Overall 0.033% 532/1,612,024 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.401%	250
Admixed American	0.0751%	1,332
Middle Eastern	0.0604%	1,657
Remaining individualsnot grpmax-eligible	0.0593%	1,685
Finnishnot grpmax-eligible	0.0157%	6,389
European (non-Finnish)	0.0109%	9,145
South Asian	0.0088%	11,365

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.His338=
Coding: c.1014C>T
MANE Select: NM_001609
dbSNP: rs57339164
Type: single nucleotide variant
Location: chr10:123051072 (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 338: an α-helix

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.His338Gln Uncertain significance ★ ⚠ 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-his338 (accessed [today's date]).

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