Is ACAD9 p.Arg559Ser (c.1675C>A) pathogenic?

ACAD9 p.Arg559Ser (c.1675C>A) is classified Benign/Likely benign in ACAD9 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.369); Rare (popmax 0.869%, eas); Associated with acyl-CoA dehydrogenase 9 deficiency.

What condition is associated with ACAD9 p.Arg559Ser (c.1675C>A)?

ACAD9 p.Arg559Ser (c.1675C>A) is associated with acyl-CoA dehydrogenase 9 deficiency (ClinVar).

How common is ACAD9 p.Arg559Ser (c.1675C>A) in the general population?

ACAD9 p.Arg559Ser (c.1675C>A) is rare (popmax 0.869%, eas) (gnomAD).

How is Acyl-CoA dehydrogenase 9 deficiency inherited?

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

What do computational predictors say about ACAD9 p.Arg559Ser (c.1675C>A)?

AlphaMissense predicts ambiguous (score 0.369) — an in-silico prediction, not a clinical call.

ACAD9 p.Arg559Ser

c.1675C>A · rs138871762 · VCV343206

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.369 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.869%, eas)

Conditions

acyl-CoA dehydrogenase 9 deficiency

Computational evidence

Protein change
AlphaMissense	0.369	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -5.99	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP 0.68
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	14.68	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 0.869% East Asian · 390/44,882 alleles

Filtering AF 0.798% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.77%

Overall 0.0266% 430/1,614,056 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.869%	115
Remaining individualsnot grpmax-eligible	0.032%	3,125
South Asian	0.0121%	8,279
Admixed American	0.00333%	30,009
African / African-American	0.00133%	75,066
European (non-Finnish)	0.000508%	196,673

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: ACAD9
Protein: p.Arg559Ser
Coding: c.1675C>A
MANE Select: NM_014049
dbSNP: rs138871762
Type: single nucleotide variant
Location: chr3:128910132 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09 · 2 PDB

Full ACAD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acyl-CoA dehydrogenase 9 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Acyl-CoA dehydrogenase 9 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ACAD9 p.Arg559Cys Uncertain significance ★★ ⚠ same residue
ACAD9 p.Arg559His Uncertain significance ★ ⚠ same residue
ACAD9 c.1150-2A>G Likely pathogenic ★★ same condition
ACAD9 c.1278+1G>T Likely pathogenic ★★ same condition
ACAD9 c.1279-2A>C Likely pathogenic ★★ same condition
ACAD9 c.1358+2T>G Likely pathogenic ★★ same condition
ACAD9 c.1359-1G>A Pathogenic/Likely pathogenic ★★ same condition
ACAD9 c.1563+1G>A 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/acad9-p-arg559ser (accessed [today's date]).

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