# NM_000019.4(ACAT1):c.49C>T (p.Pro17Ser)

https://sugi.bio/variant/acat1-p-pro17ser

## Summary

**ACAT1 p.Pro17Ser (c.49C>T)** is classified **Uncertain significance** in ACAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: likely benign (0.0836); Very rare (popmax 0.00357%, sas); Associated with beta-ketothiolase deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs573208198 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00357%, sas)

## For patients & families {#patients}

This is a change in the ACAT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to beta-ketothiolase 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) | Childhood, Infancy, Neonatal |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Beta-ketothiolase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Acidosis — Very frequent (99-80%)
- Metabolic acidosis — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Vomiting — Very frequent (99-80%)
- Hyperuricemia — Very frequent (99-80%)
- Tachypnea — Very frequent (99-80%)
- Ketonuria — Very frequent (99-80%)
- Abnormality of higher mental function — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000872/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACAT1](https://sugi.bio/atlas/gene/ACAT1/) |
| Protein change (HGVS p.) | p.Pro17Ser |
| Coding change (HGVS c.) | c.49C>T |
| MANE Select transcript | [NM_003101](https://www.ncbi.nlm.nih.gov/nuccore/NM_003101) (variant reported on NM_000019) |
| dbSNP | [rs573208198](https://www.ncbi.nlm.nih.gov/snp/rs573208198/) |
| Variant type | single nucleotide variant |
| Location | chr11:108121655-108121655 (GRCh38) |
| ClinVar | [VCV1933446](https://www.ncbi.nlm.nih.gov/clinvar/variation/1933446/) |

**All HGVS expressions:** `LRG_1400:g.9951C>T`, `LRG_1400t1:c.49C>T`, `NC_000011.10:g.108121655C>T`, `NC_000011.9:g.107992382C>T`, `NG_009888.2:g.9951C>T`, `NM_000019.4:c.49C>T`, `NM_001386677.1:c.49C>T`, `NM_001386678.1:c.49C>T`, `NM_001386679.1:c.-229C>T`, `NM_001386681.1:c.-199+4753C>T`, `NM_001386682.1:c.-416+4753C>T`, `NM_001386685.1:c.-316C>T`, `NM_001386686.1:c.-321C>T`, `NR_170162.1:n.89C>T`, `NR_170163.1:n.89C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0836)
- REVEL 0.281 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -0.926 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.119, GERP -3.01 — weakly conserved position
- CADD: **PHRED 13.67**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00357%** (sas) · FAF95 0.000948% · FAF99 0.000463% · 3/84,076 in the highest group · 6/1,549,844 alleles overall — very rare (popmax 0.00357%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.005% | 20,003 |
| South Asian (grpmax) | 0.00357% | 28,025 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


Curated gene–disease validity (ClinGen):

- **beta-ketothiolase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **17** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 81.22, 51% of residues very-high.

**5 experimental structure(s)** (PDB): [6L47](https://www.rcsb.org/structure/6L47), [6L48](https://www.rcsb.org/structure/6L48), [6P2J](https://www.rcsb.org/structure/6P2J), [6P2P](https://www.rcsb.org/structure/6P2P), [6VUM](https://www.rcsb.org/structure/6VUM).

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

*Describes the biological roles of ACAT1 (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:** ACAT1's established molecular role includes fatty-acyl-CoA binding. p.Pro17Ser falls in the disordered region.


### Pathways affected {#pathways}

ACAT1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | curated |

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

**Molecular function:** fatty-acyl-CoA binding, sterol O-acyltransferase activity, cholesterol binding, cholesterol O-acyltransferase activity, identical protein binding.

**Biological process:** cholesterol metabolic process, macrophage derived foam cell differentiation, cholesterol storage, cholesterol efflux, very-low-density lipoprotein particle assembly, cholesterol homeostasis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-20 |

## Associated conditions {#conditions}

[beta-ketothiolase deficiency](https://sugi.bio/atlas/disease/beta-ketothiolase-deficiency/).

**Reported phenotype names (ClinVar):** Deficiency of acetyl-CoA acetyltransferase, 3-KETOTHIOLASE DEFICIENCY, 3-OXOTHIOLASE DEFICIENCY, Beta-ketothiolase deficiency, MITOCHONDRIAL ACETOACETYL-CoA THIOLASE DEFICIENCY.

## Similar variants {#similar}

Related ACAT1 variant pages (same residue, condition, or type): [ACAT1 p.Pro17Ala](/variant/acat1-p-pro17ala), [ACAT1 p.Pro17=](/variant/acat1-p-pro17), [ACAT1 c.1006-1G>A](/variant/acat1-c-1006-minus-1g-a), [ACAT1 c.1006-1G>C](/variant/acat1-c-1006-minus-1g-c), [ACAT1 c.1006-2A>C](/variant/acat1-c-1006-minus-2a-c), [ACAT1 c.1163+2T>C](/variant/acat1-c-1163-plus-2t-c), [ACAT1 c.120+1G>C](/variant/acat1-c-120-plus-1g-c), [ACAT1 c.121-3C>G](/variant/acat1-c-121-minus-3c-g).

### 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 1933446). 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.*