Is ACAD8 p.Arg7Pro (c.20G>C) pathogenic?

ACAD8 p.Arg7Pro (c.20G>C) is classified Benign in ACAD8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1347); Low-frequency (popmax 3.48%, afr); Associated with isobutyryl-CoA dehydrogenase deficiency.

What condition is associated with ACAD8 p.Arg7Pro (c.20G>C)?

ACAD8 p.Arg7Pro (c.20G>C) is associated with isobutyryl-CoA dehydrogenase deficiency (ClinVar).

How common is ACAD8 p.Arg7Pro (c.20G>C) in the general population?

ACAD8 p.Arg7Pro (c.20G>C) is low-frequency (popmax 3.48%, afr) (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.Arg7Pro (c.20G>C)?

AlphaMissense predicts likely benign (score 0.1347) — an in-silico prediction, not a clinical call.

ACAD8 p.Arg7Pro

c.20G>C · rs35181923 · VCV95584

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1347 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.48%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isobutyryl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.1347	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.083	GERP -4.3
Regional constraint	o/e 0.92	unconstrained · MANE · 11 kb · p 0.076 · regional, not allelic
Overall
CADD	7.094	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 3.48% African / African-American · 2,582/74,250 alleles

Filtering AF 3.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.32%

Overall 0.193% 3,043/1,579,502 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.48%	29
Middle Eastern	0.333%	300
Remaining individualsnot grpmax-eligible	0.282%	354
Admixed American	0.255%	392
European (non-Finnish)	0.0103%	9,721
South Asian	0.00687%	14,558
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,990

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.Arg7Pro
Coding: c.20G>C
MANE Select: NM_014384
dbSNP: rs35181923
Type: single nucleotide variant
Location: chr11:134253620 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.19 · 1 PDB

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.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
ACAD8 c.940-13C>G 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-arg7pro (accessed [today's date]).

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