Is ACAT1 p.Pro326= (c.978A>C) pathogenic?

ACAT1 p.Pro326= (c.978A>C) is classified Benign in ACAT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-31). Low-frequency (popmax 3.36%, afr); Associated with beta-ketothiolase deficiency.

What condition is associated with ACAT1 p.Pro326= (c.978A>C)?

ACAT1 p.Pro326= (c.978A>C) is associated with beta-ketothiolase deficiency (ClinVar).

How common is ACAT1 p.Pro326= (c.978A>C) in the general population?

ACAT1 p.Pro326= (c.978A>C) is low-frequency (popmax 3.36%, afr) (gnomAD).

How is Beta-ketothiolase deficiency inherited?

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

ACAT1 p.Pro326=

c.978A>C · rs73559264 · VCV302204

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.36%, afr)

Conditions

beta-ketothiolase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -3.1
Overall
CADD	6.958	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.36% African / African-American · 2,187/65,164 alleles

Filtering AF 3.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.19%

Overall 0.184% 2,551/1,383,334 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.36%	30
Remaining individualsnot grpmax-eligible	0.306%	327
Admixed American	0.237%	423
Middle Eastern	0.184%	544
Finnishnot grpmax-eligible	0.0186%	5,386
European (non-Finnish)	0.00705%	14,194
South Asian	0.00454%	22,048
East Asian	0.00412%	24,288

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.Pro326=
Coding: c.978A>C
MANE Select: NM_003101 · reported on NM_000019
dbSNP: rs73559264
Type: single nucleotide variant
Location: chr11:108144020 (GRCh38)
Structure: AlphaFold pLDDT 81.22 · 5 PDB
Residue 326: an α-helix

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.Pro326Ala Uncertain significance ★ ⚠ same residue
ACAT1 p.Pro326Leu Uncertain significance ★ ⚠ same residue
ACAT1 c.1006-1G>A Pathogenic ★★ same condition
ACAT1 c.1006-1G>C Pathogenic ★★ same condition
ACAT1 c.1006-2A>C Pathogenic ★★ same condition
ACAT1 c.1163+2T>C Pathogenic ★★ same condition
ACAT1 c.120+1G>C Likely pathogenic ★★ same condition
ACAT1 c.121-3C>G Pathogenic/Likely 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-pro326 (accessed [today's date]).

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