# NM_001093.4(ACACB):c.4335C>T (p.Phe1445=)

https://sugi.bio/variant/acacb-p-phe1445

## Summary

**ACACB p.Phe1445= (c.4335C>T)** is classified **Benign** in ACACB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). Low-frequency (popmax 1.72%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs115320291 · 3 submitters · low-frequency (popmax 1.72%, afr)

## For patients & families {#patients}

This is a change in the ACACB gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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 | [ACACB](https://sugi.bio/atlas/gene/ACACB/) |
| Protein change (HGVS p.) | p.Phe1445= |
| Coding change (HGVS c.) | c.4335C>T |
| MANE Select transcript | [NM_001093](https://www.ncbi.nlm.nih.gov/nuccore/NM_001093) |
| dbSNP | [rs115320291](https://www.ncbi.nlm.nih.gov/snp/rs115320291/) |
| Variant type | single nucleotide variant |
| Location | chr12:109234033-109234033 (GRCh38) |
| ClinVar | [VCV727380](https://www.ncbi.nlm.nih.gov/clinvar/variation/727380/) |

**All HGVS expressions:** `NC_000012.11:g.109671838C>T`, `NC_000012.12:g.109234033C>T`, `NG_046907.1:g.127850C>T`, `NM_001093.4:c.4335C>T`

## 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 -12.468, GERP -3.55 — fast-evolving / accelerated position
- CADD: **PHRED 0.32**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.55 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.72%** (afr) · FAF95 1.64% · FAF99 1.61% · 1,289/75,014 in the highest group · 1,676/1,611,894 alleles overall — low-frequency (popmax 1.72%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.72% | 58 |
| Middle Eastern | 0.448% | 223 |
| Remaining individuals (not grpmax-eligible) | 0.139% | 718 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.122% | 821 |
| Admixed American | 0.104% | 964 |
| European (non-Finnish) | 0.0147% | 6,814 |
| South Asian | 0.00221% | 45,280 |

*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}

**ACACB** population constraint: LOEUF 0.843, pLI 2.7387e-49, missense-Z 3.1108. *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 79.29, 29% of residues very-high.

**11 experimental structure(s)** (PDB): [2DN8](https://www.rcsb.org/structure/2DN8), [2HJW](https://www.rcsb.org/structure/2HJW), [2KCC](https://www.rcsb.org/structure/2KCC), [3FF6](https://www.rcsb.org/structure/3FF6), [3GID](https://www.rcsb.org/structure/3GID), [3GLK](https://www.rcsb.org/structure/3GLK).

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

*Describes the biological roles of ACACB (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:** ACACB's established molecular role includes acetyl-CoA carboxylase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |

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

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

**Biological process:** acetyl-CoA metabolic process, protein homotetramerization.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-12-31.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-04-11 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, ACACB-related disorder, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, ACACB-related condition.

## Similar variants {#similar}

Related ACACB variant pages (same residue, condition, or type): [ACACB p.Val958Met](/variant/acacb-p-val958met), [ACACB c.6942+9C>T](/variant/acacb-c-6942-plus-9c-t), [ACACB c.6943-8G>A](/variant/acacb-c-6943-minus-8g-a), [ACACB c.7113+7C>T](/variant/acacb-c-7113-plus-7c-t), [ACACB p.Ala650=](/variant/acacb-p-ala650), [ACACB p.Arg1786Gln](/variant/acacb-p-arg1786gln), [ACACB p.Asp1481Val](/variant/acacb-p-asp1481val), [ACACB p.Gln1257Glu](/variant/acacb-p-gln1257glu).

### 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 727380). 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.*