# NM_000016.6(ACADM):c.136_158dup (p.Phe55fs)

https://sugi.bio/variant/acadm-p-phe55fs

## Summary

**ACADM p.Phe55fs (c.136_158dup)** is classified **Pathogenic** in ACADM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-25). Very rare (popmax 8.48e-05%, nfe); Associated with medium chain acyl-CoA dehydrogenase deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2525572068 · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the ACADM gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to medium 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) | Infancy, Neonatal |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 13 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACADM is a diagnostic-grade gene on 13 Genomics England panels |

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

- Hypotonia — Frequent (79-30%)
- Reduced tendon reflexes — Frequent (79-30%)
- Decreased liver function — Frequent (79-30%)
- Hyperammonemia — Frequent (79-30%)
- Vomiting — Frequent (79-30%)
- Hepatomegaly — Frequent (79-30%)
- Dicarboxylic aciduria — Frequent (79-30%)
- Fatigable weakness — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000540/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACADM](https://sugi.bio/atlas/gene/ACADM/) |
| Protein change (HGVS p.) | p.Phe55fs |
| Coding change (HGVS c.) | c.136_158dup |
| MANE Select transcript | [NM_000016](https://www.ncbi.nlm.nih.gov/nuccore/NM_000016) |
| dbSNP | [rs2525572068](https://www.ncbi.nlm.nih.gov/snp/rs2525572068/) |
| Variant type | Duplication |
| Location | chr1:75732659-75732660 (GRCh38) |
| ClinVar | [VCV2420712](https://www.ncbi.nlm.nih.gov/clinvar/variation/2420712/) |

**All HGVS expressions:** `LRG_838:g.13304_13326dup`, `LRG_838t1:c.136_158dup`, `NC_000001.10:g.76198346_76198368dup`, `NC_000001.11:g.75732661_75732683dup`, `NG_007045.2:g.13304_13326dup`, `NM_000016.6:c.136_158dup`, `NM_001127328.3:c.148_170dup`, `NM_001286042.2:c.28_50dup`, `NM_001286043.2:c.136_158dup`, `NM_001286044.2:c.-250_-228dup`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.155, GERP 1.69, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.072, pLI 6.8458e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,834 in the highest group · 1/1,461,578 alleles overall — very rare (popmax 8.48e-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}

**ACADM** population constraint: LOEUF 1.072, pLI 6.8458e-12, missense-Z 0.42409; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

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

## Protein context {#protein}

Residue **55** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.15, 91% of residues very-high.

**7 experimental structure(s)** (PDB): [1EGC](https://www.rcsb.org/structure/1EGC), [1EGD](https://www.rcsb.org/structure/1EGD), [1EGE](https://www.rcsb.org/structure/1EGE), [1T9G](https://www.rcsb.org/structure/1T9G), [2A1T](https://www.rcsb.org/structure/2A1T), [4P13](https://www.rcsb.org/structure/4P13) — incl. mutant structure 1EGC.

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

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


### Pathways affected {#pathways}

ACADM participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA](https://reactome.org/content/detail/R-HSA-77346) | curated |
| [Beta oxidation of octanoyl-CoA to hexanoyl-CoA](https://reactome.org/content/detail/R-HSA-77348) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |
| [mitochondrial fatty acid beta-oxidation of unsaturated fatty acids](https://reactome.org/content/detail/R-HSA-77288) | curated |

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

**Molecular function:** acyl-CoA dehydrogenase activity, identical protein binding, medium-chain fatty acyl-CoA dehydrogenase activity.

**Biological process:** fatty acid beta-oxidation, carnitine metabolic process, CoA-linked, fatty acid beta-oxidation using acyl-CoA dehydrogenase, carnitine biosynthetic process, medium-chain fatty acid metabolic process, medium-chain fatty acid catabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-25.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Medium-chain acyl-coenzyme A dehydrogenase deficiency, MCADD, MCADH DEFICIENCY, Medium chain acyl-CoA dehydrogenase deficiency, ACADM DEFICIENCY, CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY, MCAD Deficiency.

## Same-residue context {#hotspot}

Residue **55** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ACADM p.Phe55Leu](/variant/acadm-p-phe55leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ACADM variant pages (same residue, condition, or type): [ACADM p.Phe55Leu](/variant/acadm-p-phe55leu), [ACADM p.Phe55=](/variant/acadm-p-phe55), [ACADM c.1194+1dup](/variant/acadm-c-1194-plus-1dup), [ACADM p.Ala372fs](/variant/acadm-p-ala372fs), [ACADM p.Gly115fs](/variant/acadm-p-gly115fs), [ACADM p.Gly310fs](/variant/acadm-p-gly310fs), [ACADM p.Ile78fs](/variant/acadm-p-ile78fs), [ACADM p.Leu128fs](/variant/acadm-p-leu128fs).

### 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 2420712). 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.*