# NM_000017.4(ACADS):c.988C>T (p.Arg330Cys)

https://sugi.bio/variant/acads-p-arg330cys

## Summary

**ACADS p.Arg330Cys (c.988C>T)** is classified **Pathogenic/Likely pathogenic** in ACADS (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-20). AlphaMissense: ambiguous (0.4676); Rare (popmax 0.135%, afr); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs140853839 · 11 submitters · 2 linked conditions · AlphaMissense ambiguous · rare (popmax 0.135%, afr)

## For patients & families {#patients}

This is a change in the ACADS gene that is considered likely disease-causing, submitted by 11 submitters, and is linked to Inborn genetic diseases.

*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 | [ACADS](https://sugi.bio/atlas/gene/ACADS/) |
| Protein change (HGVS p.) | p.Arg330Cys |
| Coding change (HGVS c.) | c.988C>T |
| MANE Select transcript | [NM_000017](https://www.ncbi.nlm.nih.gov/nuccore/NM_000017) |
| dbSNP | [rs140853839](https://www.ncbi.nlm.nih.gov/snp/rs140853839/) |
| Variant type | single nucleotide variant |
| Location | chr12:120738874-120738874 (GRCh38) |
| ClinVar | [VCV203557](https://www.ncbi.nlm.nih.gov/clinvar/variation/203557/) |

**All HGVS expressions:** `NC_000012.11:g.121176677C>T`, `NC_000012.12:g.120738874C>T`, `NG_007991.1:g.18107C>T`, `NM_000017.4:c.988C>T`, `NM_001302554.2:c.976C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4676) — no call either way
- REVEL 0.929 (moderately pathogenic-leaning)
- SaProt LLR -13.111 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 3.254, GERP 1.94, phastCons 1 — highly conserved
- CADD: **PHRED 31.0**. 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 0.91** across the covering region of the MANE Select transcript (120,725,886–120,739,445), spanning 13,559 bp. Chi-square p 0.038. 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 **0.135%** (afr) · FAF95 0.113% · FAF99 0.105% · 101/75,052 in the highest group · 141/1,613,868 alleles overall — rare (popmax 0.135%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.135% | 743 |
| Admixed American | 0.0183% | 5,458 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,813 |
| South Asian | 0.00549% | 18,216 |
| East Asian | 0.00223% | 44,876 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,724 |
| European (non-Finnish) | 0.00119% | 84,286 |

*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}

**ACADS** population constraint: LOEUF 0.852, pLI 3.5192e-06, missense-Z 0.79366. *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):

- **short chain acyl-CoA dehydrogenase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **330** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.58, 91% of residues very-high.

**4 experimental structure(s)** (PDB): [2VIG](https://www.rcsb.org/structure/2VIG), [7Y0A](https://www.rcsb.org/structure/7Y0A), [7Y0B](https://www.rcsb.org/structure/7Y0B), [8SGS](https://www.rcsb.org/structure/8SGS).

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

*Describes the biological roles of ACADS (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:** ACADS's established molecular role includes acyl-CoA dehydrogenase activity.


### Pathways affected {#pathways}

ACADS participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta oxidation of butanoyl-CoA to acetyl-CoA](https://reactome.org/content/detail/R-HSA-77352) | curated |
| [Beta oxidation of hexanoyl-CoA to butanoyl-CoA](https://reactome.org/content/detail/R-HSA-77350) | curated |

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

**Molecular function:** acyl-CoA dehydrogenase activity.

**Biological process:** fatty acid beta-oxidation using acyl-CoA dehydrogenase.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-20.

**Submitter consensus:** conflicting (8 Likely pathogenic, 2 Pathogenic).

**Submission history:** 13 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-23 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-15 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2016-12-21 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-20 |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-10-15 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-08 |
| Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-15 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [short chain acyl-CoA dehydrogenase deficiency](https://sugi.bio/atlas/disease/short-chain-acyl-coa-dehydrogenase-deficiency/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Deficiency of butyryl-CoA dehydrogenase, See cases, Colon adenocarcinoma, Familial cancer of breast, Lung cancer, none provided, ACADS DEFICIENCY, Short-Chain Acyl-CoA Dehydrogenase Deficiency.

## Same-residue context {#hotspot}

Residue **330** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ACADS p.Arg330His](/variant/acads-p-arg330his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ACADS variant pages (same residue, condition, or type): [ACADS p.Arg330=](/variant/acads-p-arg330), [ACADS p.Arg330His](/variant/acads-p-arg330his), [ACADS p.Arg330Leu](/variant/acads-p-arg330leu), [ACADS c.211-2A>G](/variant/acads-c-211-minus-2a-g), [ACADS c.625-1G>A](/variant/acads-c-625-minus-1g-a), [ACADS c.795+1G>A](/variant/acads-c-795-plus-1g-a), [ACADS p.Ala199Val](/variant/acads-p-ala199val), [ACADS p.Arg107Cys](/variant/acads-p-arg107cys).

### 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 203557). 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.*