# NM_198834.3(ACACA):c.441del (p.Arg148fs)

https://sugi.bio/variant/acaca-p-arg148fs

## Summary

**ACACA p.Arg148fs (c.441del)** is classified **Uncertain significance** in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the ACACA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ACACA](https://sugi.bio/atlas/gene/ACACA/) |
| Protein change (HGVS p.) | p.Arg148fs |
| Coding change (HGVS c.) | c.441del |
| MANE Select transcript | [NM_198834](https://www.ncbi.nlm.nih.gov/nuccore/NM_198834) |
| Variant type | Deletion |
| Location | chr17:37284868-37284868 (GRCh38) |
| ClinVar | [VCV4934832](https://www.ncbi.nlm.nih.gov/clinvar/variation/4934832/) |

**All HGVS expressions:** `NC_000017.10:g.35641769del`, `NC_000017.11:g.37284868del`, `NG_023295.2:g.126944del`, `NM_198834.3:c.441del`, `NM_198836.3:c.330del`, `NM_198837.2:c.156del`, `NM_198838.2:c.96del`, `NM_198839.3:c.330del`

## 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 11.789, GERP 1.98, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.374, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 56**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**ACACA** population constraint: LOEUF 0.374, pLI 1, missense-Z 10.233. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **148** lies in the biotin carboxylation domain.

AlphaFold model confidence (whole protein): pLDDT 83.05, 41% of residues very-high.

**10 experimental structure(s)** (PDB): [2YL2](https://www.rcsb.org/structure/2YL2), [3COJ](https://www.rcsb.org/structure/3COJ), [4ASI](https://www.rcsb.org/structure/4ASI), [6G2D](https://www.rcsb.org/structure/6G2D), [6G2H](https://www.rcsb.org/structure/6G2H), [6G2I](https://www.rcsb.org/structure/6G2I).

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

*Describes the biological roles of ACACA (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:** ACACA's established molecular role includes acetyl-CoA carboxylase activity. p.Arg148fs falls in the biotin carboxylation domain. In Reactome, ACACA is annotated in disease pathway(s) including **Defective HLCS causes multiple carboxylase deficiency**.

**Disease mechanism (Reactome):** ACACA loss or alteration is curated in [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599).

### Pathways affected {#pathways}

ACACA participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599) | curated |
| [Activation of gene expression by SREBF (SREBP)](https://reactome.org/content/detail/R-HSA-2426168) | curated |
| [Biotin transport and metabolism](https://reactome.org/content/detail/R-HSA-196780) | curated |
| [Carnitine shuttle](https://reactome.org/content/detail/R-HSA-200425) | curated |
| [ChREBP activates metabolic gene expression](https://reactome.org/content/detail/R-HSA-163765) | curated |
| [Fatty acyl-CoA biosynthesis](https://reactome.org/content/detail/R-HSA-75105) | curated |

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

**Molecular function:** acetyl-CoA carboxylase activity, identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-11 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ACACA variant pages (same residue, condition, or type): [ACACA p.Arg148Cys](/variant/acaca-p-arg148cys), [ACACA p.Gly1985fs](/variant/acaca-p-gly1985fs), [ACACA c.1120-19del](/variant/acaca-c-1120-minus-19del), [ACACA c.1500+11del](/variant/acaca-c-1500-plus-11del), [ACACA c.4114-10_4114-6del](/variant/acaca-c-4114-minus-10-4114-minus-6del), [ACACA p.Pro699fs](/variant/acaca-p-pro699fs), [ACACA c.4777-8del](/variant/acaca-c-4777-minus-8del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 4934832). 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.*