Is ACAD9 p.Ala326Pro (c.976G>C) pathogenic?

ACAD9 p.Ala326Pro (c.976G>C) is classified Pathogenic/Likely pathogenic in ACAD9 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-08-20). AlphaMissense: likely pathogenic (0.9792); Ultra-rare (popmax 0.017%, nfe); Associated with Possible mitochondrial disorder - nuclear genes.

What condition is associated with ACAD9 p.Ala326Pro (c.976G>C)?

ACAD9 p.Ala326Pro (c.976G>C) is associated with Possible mitochondrial disorder - nuclear genes, acyl-CoA dehydrogenase 9 deficiency, mitochondrial complex I deficiency (ClinVar).

How common is ACAD9 p.Ala326Pro (c.976G>C) in the general population?

ACAD9 p.Ala326Pro (c.976G>C) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

What do computational predictors say about ACAD9 p.Ala326Pro (c.976G>C)?

AlphaMissense predicts likely pathogenic (score 0.9792) — an in-silico prediction, not a clinical call.

ACAD9 p.Ala326Pro

c.976G>C · rs115532916 · VCV30883

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Possible mitochondrial disorder - nuclear genes

Computational evidence

Protein change
AlphaMissense	0.9792	likely pathogenic ✓ concordant with ClinVar · top 3% in ACAD9
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -13.55	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 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	28.1	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 0.017% European (non-Finnish) · 201/1,180,030 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0128% 206/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.017%	5,871
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	60,002
Finnishnot grpmax-eligible	0.00156%	64,026
African / African-American	0.00133%	74,924

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.Ala326Pro
Coding: c.976G>C
MANE Select: NM_014049
dbSNP: rs115532916
Type: single nucleotide variant
Location: chr3:128904079 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09 · 2 PDB
Residue 326: a UniProt-annotated variant site (in mc1dn20; likely benign); an α-helix

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

Disease context

Possible mitochondrial disorder - nuclear genes

Also linked: acyl-CoA dehydrogenase 9 deficiency mitochondrial complex I deficiency

Similar variants

ACAD9 p.Ala326Thr Benign/Likely benign ★★ ⚠ same residue
ACAD9 p.Ala326Ser Uncertain significance ★ ⚠ same residue
ACAD9 c.1030-1G>A Pathogenic/Likely pathogenic ★★ same condition
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

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-ala326pro (accessed [today's date]).

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