Is ACAD9 p.Glu596Lys (c.1786G>A) pathogenic?

ACAD9 p.Glu596Lys (c.1786G>A) is classified Uncertain significance in ACAD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-04). AlphaMissense: likely benign (0.0738); Very rare (popmax 0.00223%, eas); Associated with acyl-CoA dehydrogenase 9 deficiency.

What condition is associated with ACAD9 p.Glu596Lys (c.1786G>A)?

ACAD9 p.Glu596Lys (c.1786G>A) is associated with acyl-CoA dehydrogenase 9 deficiency (ClinVar).

How common is ACAD9 p.Glu596Lys (c.1786G>A) in the general population?

ACAD9 p.Glu596Lys (c.1786G>A) is very rare (popmax 0.00223%, 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.Glu596Lys (c.1786G>A)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

ACAD9 p.Glu596Lys

c.1786G>A · VCV3707164

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acyl-CoA dehydrogenase 9 deficiency

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -7.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.2	GERP 0.54, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	17.57	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00223% East Asian · 1/44,870 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,461,444 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,870
South Asian	0.0011%	91,070
European (non-Finnish)	0.00017%	589,803

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.Glu596Lys
Coding: c.1786G>A
MANE Select: NM_001394090 · reported on NM_014049
Type: single nucleotide variant
Location: chr3:128912527 (GRCh38)

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

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-glu596lys (accessed [today's date]).

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