Is ACAT1 p.Ser390Pro (c.1168T>C) pathogenic?

ACAT1 p.Ser390Pro (c.1168T>C) is classified Likely pathogenic in ACAT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-06). AlphaMissense: likely pathogenic (0.9813); Very rare (popmax 0.00017%, nfe); Associated with beta-ketothiolase deficiency.

What condition is associated with ACAT1 p.Ser390Pro (c.1168T>C)?

ACAT1 p.Ser390Pro (c.1168T>C) is associated with beta-ketothiolase deficiency (ClinVar).

How common is ACAT1 p.Ser390Pro (c.1168T>C) in the general population?

ACAT1 p.Ser390Pro (c.1168T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Beta-ketothiolase deficiency inherited?

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

What do computational predictors say about ACAT1 p.Ser390Pro (c.1168T>C)?

AlphaMissense predicts likely pathogenic (score 0.9813) — an in-silico prediction, not a clinical call.

ACAT1 p.Ser390Pro

c.1168T>C · rs1184088336 · VCV666532

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-ketothiolase deficiency

Computational evidence

Protein change
AlphaMissense	0.9813	likely pathogenic ✓ concordant with ClinVar · top 6% in ACAT1
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -14.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,900 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,610 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.Ser390Pro
Coding: c.1168T>C
MANE Select: NM_003101 · reported on NM_000019
dbSNP: rs1184088336
Type: single nucleotide variant
Location: chr11:108147274 (GRCh38)
Structure: AlphaFold pLDDT 81.22 · 5 PDB
Residue 390: 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 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
ACAT1 c.238+2T>A Pathogenic/Likely pathogenic ★★ same condition
ACAT1 c.435+1G>A 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-ser390pro (accessed [today's date]).

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