# NM_198834.3(ACACA):c.2094del (p.Pro699fs)

https://sugi.bio/variant/acaca-p-pro699fs

## Summary

**ACACA p.Pro699fs (c.2094del)** is classified **Uncertain significance** in ACACA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-21). Very rare (popmax 0.00034%, nfe); Associated with ACACA-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.00034%, nfe)

## 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, and is linked to ACACA-related disorder.

*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.Pro699fs |
| Coding change (HGVS c.) | c.2094del |
| MANE Select transcript | [NM_198834](https://www.ncbi.nlm.nih.gov/nuccore/NM_198834) |
| Variant type | Deletion |
| Location | chr17:37248662-37248662 (GRCh38) |
| ClinVar | [VCV3358815](https://www.ncbi.nlm.nih.gov/clinvar/variation/3358815/) |

**All HGVS expressions:** `NC_000017.10:g.35605587del`, `NC_000017.11:g.37248663del`, `NG_023295.2:g.163150del`, `NM_198834.3:c.2094del`, `NM_198836.3:c.1983del`, `NM_198837.2:c.1809del`, `NM_198838.2:c.1749del`, `NM_198839.3:c.1983del`

## 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 5.166, GERP 0.126, 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 17 of 56**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 29.4**. 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.*
- 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.
- Population frequency (gnomAD v4.1): grpmax **0.00034%** (nfe) · FAF95 8e-05% · FAF99 5.4e-05% · 4/1,177,006 in the highest group · 4/1,609,840 alleles overall — very rare (popmax 0.00034%, 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}

**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}


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. 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 No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-06-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-06-21 |

## Associated conditions {#conditions}

[ACACA-related disorder](https://sugi.bio/atlas/disease/acaca-related-disorder/).

**Reported phenotype names (ClinVar):** ACACA-related disorder, ACACA-related condition.

## Similar variants {#similar}

Related ACACA variant pages (same residue, condition, or type): [ACACA c.4777-8del](/variant/acaca-c-4777-minus-8del), [ACACA c.5569-10C>G](/variant/acaca-c-5569-minus-10c-g), [ACACA p.Asn990=](/variant/acaca-p-asn990), [ACACA p.Leu1734=](/variant/acaca-p-leu1734), [ACACA p.Ser789=](/variant/acaca-p-ser789), [ACACA p.Val2008=](/variant/acaca-p-val2008), [ACACA p.Arg148fs](/variant/acaca-p-arg148fs), [ACACA p.Gly1985fs](/variant/acaca-p-gly1985fs).

### 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 3358815). 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.*