Is ACADSB p.Trp207Ter (c.621G>A) pathogenic?

ACADSB p.Trp207Ter (c.621G>A) is classified Pathogenic/Likely pathogenic in ACADSB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-18). Ultra-rare (popmax 0.03%, amr); Associated with ACADSB-related disorder.

What condition is associated with ACADSB p.Trp207Ter (c.621G>A)?

ACADSB p.Trp207Ter (c.621G>A) is associated with ACADSB-related disorder, 2-methylbutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADSB p.Trp207Ter (c.621G>A) in the general population?

ACADSB p.Trp207Ter (c.621G>A) is ultra-rare (popmax 0.03%, amr) (gnomAD).

ACADSB p.Trp207Ter

c.621G>A · rs374420253 · VCV299075

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

ACADSB-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Overall
CADD	41.0	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 0.03% Admixed American · 18/60,008 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00378% 61/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,334
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)	0.00297%	33,715
African / African-American	0.00133%	74,940

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.Trp207Ter
Coding: c.621G>A
MANE Select: NM_001609
dbSNP: rs374420253
Type: single nucleotide variant
Location: chr10:123041319 (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 207: a β-strand; a binding site

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

Disease context

ACADSB-related disorder

Also linked: 2-methylbutyryl-CoA dehydrogenase deficiency

Similar variants

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
ACADSB p.Met389Val 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-trp207ter (accessed [today's date]).

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