Is ACAD8 p.Arg58Ter (c.172C>T) pathogenic?

ACAD8 p.Arg58Ter (c.172C>T) is classified Pathogenic in ACAD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). Very rare (popmax 0.00667%, amr); Associated with isobutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACAD8 p.Arg58Ter (c.172C>T)?

ACAD8 p.Arg58Ter (c.172C>T) is associated with isobutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACAD8 p.Arg58Ter (c.172C>T) in the general population?

ACAD8 p.Arg58Ter (c.172C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

How is Isobutyryl-CoA dehydrogenase deficiency inherited?

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

ACAD8 p.Arg58Ter

c.172C>T · VCV4692000

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

isobutyryl-CoA dehydrogenase deficiency

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 2 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.39	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.7	GERP 2.4, phastCons 0.013
Overall
CADD	38.0	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 0.00667% Admixed American · 4/60,000 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000929% 15/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,000
Finnishnot grpmax-eligible	0.00156%	64,016
European (non-Finnish)	0.000847%	118,003

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: ACAD8
Protein: p.Arg58Ter
Coding: c.172C>T
MANE Select: NM_014384
Type: single nucleotide variant
Location: chr11:134256610 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.19 · 1 PDB
Residue 58: an α-helix

Full ACAD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Isobutyryl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACAD8 p.Arg58Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ACAD8 p.Arg206Ter Pathogenic ★★ same condition
ACAD8 p.Arg296Ter Pathogenic ★★ same condition
ACAD8 p.Gly377Ser Pathogenic/Likely pathogenic ★★ same condition
ACAD8 p.Gly96Ser Pathogenic ★★ ⚠ same condition
ACAD8 p.Met128Ile Pathogenic/Likely pathogenic ★★ same condition
ACAD8 p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
ACAD8 c.841+6A>C Uncertain significance ★★ 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/acad8-p-arg58ter (accessed [today's date]).

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