Is ACAT2 p.Glu322Asp (c.966A>C) pathogenic?

ACAT2 p.Glu322Asp (c.966A>C) is classified Uncertain significance in ACAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.8796); Very rare (popmax 0.00334%, amr).

How common is ACAT2 p.Glu322Asp (c.966A>C) in the general population?

ACAT2 p.Glu322Asp (c.966A>C) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about ACAT2 p.Glu322Asp (c.966A>C)?

AlphaMissense predicts likely pathogenic (score 0.8796) — an in-silico prediction, not a clinical call.

ACAT2 p.Glu322Asp

c.966A>C · VCV4215046

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8796	likely pathogenic
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -10.06	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 2.9	GERP 0.79, phastCons 1
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00334% Admixed American · 2/59,900 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,612,658 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,950
African / African-American	0.00134%	74,868
European (non-Finnish)	8.48e-05%	1,179,810

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.Glu322Asp
Coding: c.966A>C
MANE Select: NM_003578 · reported on NM_005891
Type: single nucleotide variant
Location: chr6:159778223 (GRCh38)
Structure: AlphaFold pLDDT 82.59 · 2 PDB

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

Similar variants

SOAT2 p.Ala67= Benign ★★ same type
SOAT2 p.Leu402= Benign ★★ same type
ACAT2 p.Ala230Pro Uncertain significance ★ ⚠ same type
ACAT2 p.Ala323Gly Uncertain significance ★ ⚠ same type
ACAT2 p.Ala330Val Uncertain significance ★ ⚠ same type
ACAT2 p.Ala348Ser Uncertain significance ★ ⚠ same type
ACAT2 p.Ala357Gly Uncertain significance ★ ⚠ same type
ACAT2 p.Arg223His Uncertain significance ★ ⚠ same type

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-glu322asp (accessed [today's date]).

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