Is ACAD8 p.Arg302Pro (c.905G>C) pathogenic?

ACAD8 p.Arg302Pro (c.905G>C) is classified Uncertain significance in ACAD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely pathogenic (0.9863); Very rare (popmax 0.000339%, nfe); Associated with isobutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACAD8 p.Arg302Pro (c.905G>C)?

ACAD8 p.Arg302Pro (c.905G>C) is associated with isobutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACAD8 p.Arg302Pro (c.905G>C) in the general population?

ACAD8 p.Arg302Pro (c.905G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Isobutyryl-CoA dehydrogenase deficiency inherited?

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

What do computational predictors say about ACAD8 p.Arg302Pro (c.905G>C)?

AlphaMissense predicts likely pathogenic (score 0.9863) — an in-silico prediction, not a clinical call.

ACAD8 p.Arg302Pro

c.905G>C · rs121908422 · VCV640851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isobutyryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.9863	likely pathogenic · top 3% in ACAD8
REVEL	0.988	strongly pathogenic-leaning
SaProt	LLR -16.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.076 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,044 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,892 alleles · very rare

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.Arg302Pro
Coding: c.905G>C
MANE Select: NM_014384
dbSNP: rs121908422
Type: single nucleotide variant
Location: chr11:134261338 (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 302: a UniProt-annotated variant site (in ibdd; no effect on localization to the mitochondrion; complete loss of isobutyryl-coa dehydrogenase activity; loss of protein expression in patient cells); a binding site

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.Arg302Gln 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-arg302pro (accessed [today's date]).

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