Is ACAT2 p.Glu397fs (c.1189_1190del) pathogenic?

ACAT2 p.Glu397fs (c.11891190del) is classified Uncertain significance in ACAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). Very rare (popmax 0.00333%, amr); Associated with ZTTK syndrome.

What condition is associated with ACAT2 p.Glu397fs (c.1189_1190del)?

ACAT2 p.Glu397fs (c.1189_1190del) is associated with ZTTK syndrome (ClinVar).

How common is ACAT2 p.Glu397fs (c.1189_1190del) in the general population?

ACAT2 p.Glu397fs (c.1189_1190del) is very rare (popmax 0.00333%, amr) (gnomAD).

ACAT2 p.Glu397fs

c.1189_1190del · VCV4278481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

ZTTK syndrome

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 3.3	GERP 1.7, phastCons 1
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000558% 9/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
European (non-Finnish)	0.000593%	168,576

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: ACAT2
Protein: p.Glu397fs
Coding: c.1189_1190del
MANE Select: NM_003578 · reported on NM_005891
Type: Microsatellite
Location: chr6:159778819 (GRCh38)
Structure: AlphaFold pLDDT 82.59 · 2 PDB

Full ACAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ZTTK syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/acat2-p-glu397fs (accessed [today's date]).

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