Is ACAT1 p.Ser46fs (c.134dup) pathogenic?

ACAT1 p.Ser46fs (c.134dup) is classified Pathogenic/Likely pathogenic in ACAT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). Very rare (popmax 0.00133%, afr); Associated with beta-ketothiolase deficiency.

What condition is associated with ACAT1 p.Ser46fs (c.134dup)?

ACAT1 p.Ser46fs (c.134dup) is associated with beta-ketothiolase deficiency (ClinVar).

How common is ACAT1 p.Ser46fs (c.134dup) in the general population?

ACAT1 p.Ser46fs (c.134dup) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Beta-ketothiolase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ACAT1 p.Ser46fs

c.134dup · rs1444451434 · VCV1457479

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

beta-ketothiolase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,032 alleles

Overall 6.84e-05% 1/1,461,614 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACAT1
Protein: p.Ser46fs
Coding: c.134dup
MANE Select: NM_003101 · reported on NM_000019
dbSNP: rs1444451434
Type: Duplication
Location: chr11:108133832 (GRCh38)
Structure: AlphaFold pLDDT 81.22 · 5 PDB

Full ACAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

beta-ketothiolase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Beta-ketothiolase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

ACAT1 p.Ser46= Conflicting classifications of pathogenicity ★ same residue
ACAT1 p.Glu88fs Pathogenic/Likely pathogenic ★★ same condition
ACAT1 p.Gly378fs Pathogenic/Likely pathogenic ★★ same condition
ACAT1 p.Thr241fs Pathogenic ★★ same condition
ACAT1 c.*6dup Benign ★★ same condition
ACAT1 c.(730+1_731-1 Pathogenic ★ same condition
ACAT1 c.940+2dup Likely pathogenic ★ same condition
ACAT1 p.Ala111fs Pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/acat1-p-ser46fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown