# NM_014049.5(ACAD9):c.976G>C (p.Ala326Pro)

https://sugi.bio/variant/acad9-p-ala326pro

## Summary

**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.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs115532916 · 9 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.017%, nfe)

## For patients & families {#patients}

This is a change in the ACAD9 gene that is considered likely disease-causing, submitted by 9 submitters, and is linked to Possible mitochondrial disorder - nuclear genes.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACAD9](https://sugi.bio/atlas/gene/ACAD9/) |
| Protein change (HGVS p.) | p.Ala326Pro |
| Coding change (HGVS c.) | c.976G>C |
| MANE Select transcript | [NM_014049](https://www.ncbi.nlm.nih.gov/nuccore/NM_014049) |
| dbSNP | [rs115532916](https://www.ncbi.nlm.nih.gov/snp/rs115532916/) |
| Variant type | single nucleotide variant |
| Location | chr3:128904079-128904079 (GRCh38) |
| ClinVar | [VCV30883](https://www.ncbi.nlm.nih.gov/clinvar/variation/30883/) |

**All HGVS expressions:** `NC_000003.11:g.128622922G>C`, `NC_000003.12:g.128904079G>C`, `NG_017064.1:g.29590G>C`, `NM_014049.5:c.976G>C`, `NR_033426.2:n.1224G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9792) — concordant with the pathogenic call
- REVEL 0.963 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.555 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.514, GERP 1.7, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in ACAD9 (of 3,653 modeled).
- CADD: **PHRED 28.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (128,879,692–128,912,604), spanning 32,912 bp. Chi-square p 0.36. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.017%** (nfe) · FAF95 0.0151% · FAF99 0.0143% · 201/1,180,030 in the highest group · 206/1,614,058 alleles overall — ultra-rare (popmax 0.017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.017% | 5,871 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |
| Admixed American | 0.00167% | 60,002 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,026 |
| African / African-American | 0.00133% | 74,924 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ACAD9** population constraint: LOEUF 0.884, pLI 1.1413e-12, missense-Z 0.86095. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **acyl-CoA dehydrogenase 9 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **326** lies in a UniProt-annotated variant site (in mc1dn20; likely benign); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.09, 85% of residues very-high.

**2 experimental structure(s)** (PDB): [8PHE](https://www.rcsb.org/structure/8PHE), [8PHF](https://www.rcsb.org/structure/8PHF).

## What this gene does {#gene-function}

*Describes the biological roles of ACAD9 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ACAD9's established molecular role includes acyl-CoA dehydrogenase activity.


### Pathways affected {#pathways}

ACAD9 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex I biogenesis](https://reactome.org/content/detail/R-HSA-6799198) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** acyl-CoA dehydrogenase activity, long-chain fatty acyl-CoA dehydrogenase activity, very-long-chain fatty acyl-CoA dehydrogenase activity, protein-macromolecule adaptor activity, medium-chain fatty acyl-CoA dehydrogenase activity.

**Biological process:** long-chain fatty acid metabolic process, mitochondrial respiratory chain complex I assembly, medium-chain fatty acid metabolic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-20.

**Submitter consensus:** conflicting (6 Pathogenic, 3 Likely pathogenic).

**Submission history:** 9 submissions (2010–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2013-05-13 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2010-12-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-06 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-11-27 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-08-19 |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-10 |
| MGZ Medical Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-08-09 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-20 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-09 |

## Associated conditions {#conditions}

[Possible mitochondrial disorder - nuclear genes](https://sugi.bio/atlas/disease/possible-mitochondrial-disorder-nuclear-genes/), [acyl-CoA dehydrogenase 9 deficiency](https://sugi.bio/atlas/disease/acyl-coa-dehydrogenase-9-deficiency/), [mitochondrial complex I deficiency](https://sugi.bio/atlas/disease/mitochondrial-complex-i-deficiency/).

**Reported phenotype names (ClinVar):** Possible mitochondrial disorder - nuclear genes, Acyl-CoA dehydrogenase 9 deficiency, not provided, Mitochondrial complex I deficiency, ACAD9-related disorder, NADH:Q(1) OXIDOREDUCTASE DEFICIENCY, ACAD9-related condition, none provided, Acyl-CoA dehydrogenase family, member 9, deficiency of, MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 20.

## Similar variants {#similar}

Related ACAD9 variant pages (same residue, condition, or type): [ACAD9 p.Ala326Thr](/variant/acad9-p-ala326thr), [ACAD9 p.Ala326Ser](/variant/acad9-p-ala326ser), [ACAD9 c.1030-1G>A](/variant/acad9-c-1030-minus-1g-a), [ACAD9 c.1150-2A>G](/variant/acad9-c-1150-minus-2a-g), [ACAD9 c.1278+1G>T](/variant/acad9-c-1278-plus-1g-t), [ACAD9 c.1279-2A>C](/variant/acad9-c-1279-minus-2a-c), [ACAD9 c.1358+2T>G](/variant/acad9-c-1358-plus-2t-g), [ACAD9 c.1359-1G>A](/variant/acad9-c-1359-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 30883). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*