# NM_001243279.3(ACSF3):c.220dup (p.Arg74fs)

https://sugi.bio/variant/acsf3-p-arg74fs

## Summary

**ACSF3 p.Arg74fs (c.220dup)** is classified **Pathogenic** in ACSF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). No gnomAD frequency available for this variant; Associated with combined malonic and methylmalonic acidemia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2543520647 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ACSF3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to combined malonic and methylmalonic acidemia.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (United States) |
| Diagnostic panels | ACSF3 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Combined malonic and methylmalonic acidemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Methylmalonic acidemia — Very frequent (99-80%)
- Dicarboxylic aciduria — Very frequent (99-80%)
- Methylmalonic aciduria — Very frequent (99-80%)
- Dicarboxylic acidemia — Very frequent (99-80%)
- Seizure — Frequent (79-30%)
- Microcephaly — Occasional (29-5%)
- Atypical behavior — Occasional (29-5%)
- Delayed speech and language development — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010818/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACSF3](https://sugi.bio/atlas/gene/ACSF3/) |
| Protein change (HGVS p.) | p.Arg74fs |
| Coding change (HGVS c.) | c.220dup |
| MANE Select transcript | [NM_001243279](https://www.ncbi.nlm.nih.gov/nuccore/NM_001243279) |
| dbSNP | [rs2543520647](https://www.ncbi.nlm.nih.gov/snp/rs2543520647/) |
| Variant type | Duplication |
| Location | chr16:89100898-89100899 (GRCh38) |
| ClinVar | [VCV2703212](https://www.ncbi.nlm.nih.gov/clinvar/variation/2703212/) |

**All HGVS expressions:** `NC_000016.10:g.89100901dup`, `NC_000016.9:g.89167309dup`, `NG_031961.1:g.12093dup`, `NM_001127214.4:c.220dup`, `NM_001243279.3:c.220dup`, `NM_001284316.2:c.-129-1703dup`, `NM_174917.5:c.220dup`, `NR_104293.2:n.558dup`, `NR_147928.2:n.558dup`, `NR_147929.2:n.558dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -0.727, GERP -3.63 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.715, pLI 2.6577e-36. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 11**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ACSF3** population constraint: LOEUF 1.715, pLI 2.6577e-36, missense-Z -2.0014; 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):

- **combined malonic and methylmalonic acidemia** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.58, 68% of residues very-high.

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

*Describes the biological roles of ACSF3 (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:** ACSF3's established molecular role includes very long-chain fatty acid-CoA ligase activity.


### Pathways affected {#pathways}

ACSF3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of very long-chain fatty acyl-CoAs](https://reactome.org/content/detail/R-HSA-75876) | curated |

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

**Molecular function:** very long-chain fatty acid-CoA ligase activity, malonyl-CoA synthetase activity.

**Biological process:** fatty acid metabolic process, fatty acid biosynthetic process, malonate catabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-14.

**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 | 2023-12-14 |

## Associated conditions {#conditions}

[combined malonic and methylmalonic acidemia](https://sugi.bio/atlas/disease/combined-malonic-and-methylmalonic-acidemia/).

**Reported phenotype names (ClinVar):** Combined malonic and methylmalonic acidemia.

## Similar variants {#similar}

Related ACSF3 variant pages (same residue, condition, or type): [ACSF3 p.Arg74Cys](/variant/acsf3-p-arg74cys), [ACSF3 p.Arg74His](/variant/acsf3-p-arg74his), [ACSF3 p.Ala253fs](/variant/acsf3-p-ala253fs), [ACSF3 p.His526fs](/variant/acsf3-p-his526fs), [ACSF3 p.Leu522fs](/variant/acsf3-p-leu522fs), [ACSF3 p.Lys444Ter](/variant/acsf3-p-lys444ter), [ACSF3 p.Val460fs](/variant/acsf3-p-val460fs), [ACSF3 p.Val484fs](/variant/acsf3-p-val484fs).

### 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 2703212). 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.*