Is ACAT1 p.Pro17Ala (c.49C>G) pathogenic?

ACAT1 p.Pro17Ala (c.49C>G) is classified Uncertain significance in ACAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-05). AlphaMissense: likely benign (0.0748); Very rare (popmax 0.00391%, amr); Associated with beta-ketothiolase deficiency.

What condition is associated with ACAT1 p.Pro17Ala (c.49C>G)?

ACAT1 p.Pro17Ala (c.49C>G) is associated with beta-ketothiolase deficiency (ClinVar).

How common is ACAT1 p.Pro17Ala (c.49C>G) in the general population?

ACAT1 p.Pro17Ala (c.49C>G) is very rare (popmax 0.00391%, amr) (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.Pro17Ala (c.49C>G)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

ACAT1 p.Pro17Ala

c.49C>G · VCV3605221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00391%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-ketothiolase deficiency

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.29	benign-leaning
SaProt	LLR -1.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -3
Overall
CADD	13.08	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00391% Admixed American · 2/51,132 alleles

Filtering AF 0.000649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000243%

Overall 0.000143% 2/1,397,468 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.Pro17Ala
Coding: c.49C>G
MANE Select: NM_003101 · reported on NM_000019
Type: single nucleotide variant
Location: chr11:108121655 (GRCh38)
Structure: AlphaFold pLDDT 81.22 · 5 PDB
Residue 17: the 'disordered' region

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.Pro17Ser Uncertain significance ★ ⚠ same residue
ACAT1 p.Pro17= Likely benign ★ 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-pro17ala (accessed [today's date]).

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