# NM_000017.4(ACADS):c.1064C>T (p.Ala355Val)

https://sugi.bio/variant/acads-p-ala355val

## Summary

**ACADS p.Ala355Val (c.1064C>T)** is classified **Uncertain significance** in ACADS (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-23). AlphaMissense: likely benign (0.1589); Very rare (popmax 8.47e-05%, nfe); Associated with short chain acyl-CoA dehydrogenase deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs770439736 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ACADS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to short chain acyl-CoA dehydrogenase deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACADS is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Short chain acyl-CoA dehydrogenase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Failure to thrive — Frequent (79-30%)
- Metabolic acidosis — Frequent (79-30%)
- Ethylmalonic aciduria — Frequent (79-30%)
- Floppy infant — Frequent (79-30%)
- Feeding difficulties — Frequent (79-30%)
- Neurodevelopmental delay — Frequent (79-30%)
- Elevated plasma acylcarnitine levels — Frequent (79-30%)
- Increased level of methylsuccinic acid in urine — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004822/index) · [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.Ala355Val |
| Coding change (HGVS c.) | c.1064C>T |
| MANE Select transcript | [NM_000017](https://www.ncbi.nlm.nih.gov/nuccore/NM_000017) |
| dbSNP | [rs770439736](https://www.ncbi.nlm.nih.gov/snp/rs770439736/) |
| Variant type | single nucleotide variant |
| Location | chr12:120739174-120739174 (GRCh38) |
| ClinVar | [VCV565636](https://www.ncbi.nlm.nih.gov/clinvar/variation/565636/) |

**All HGVS expressions:** `NC_000012.11:g.121176977C>T`, `NC_000012.12:g.120739174C>T`, `NG_007991.1:g.18407C>T`, `NM_000017.4:c.1064C>T`, `NM_001302554.2:c.1052C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1589)
- REVEL 0.629 (indeterminate)
- SaProt LLR -9.541 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.615, GERP 1.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.3**. 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 **8.47e-05%** (nfe) · 1/1,179,996 in the highest group · 1/1,460,720 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **355** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-04-23.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-04-23 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Deficiency of butyryl-CoA dehydrogenase, Short-Chain Acyl-CoA Dehydrogenase Deficiency, SCADH DEFICIENCY, ACADS DEFICIENCY, SCAD DEFICIENCY, MILD, ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF, SCAD Deficiency.

## Similar variants {#similar}

Related ACADS variant pages (same residue, condition, or type): [ACADS p.Ala355=](/variant/acads-p-ala355), [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), [ACADS p.Arg272Cys](/variant/acads-p-arg272cys), [ACADS p.Arg325Gln](/variant/acads-p-arg325gln).

### 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 565636). 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.*