Is ACO2 p.Lys520fs (c.1559del) pathogenic?

ACO2 p.Lys520fs (c.1559del) is classified Pathogenic/Likely pathogenic in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-06). Very rare (popmax 0.00534%, afr); Associated with ACO2-related disorder.

What condition is associated with ACO2 p.Lys520fs (c.1559del)?

ACO2 p.Lys520fs (c.1559del) is associated with ACO2-related disorder (ClinVar).

How common is ACO2 p.Lys520fs (c.1559del) in the general population?

ACO2 p.Lys520fs (c.1559del) is very rare (popmax 0.00534%, afr) (gnomAD).

ACO2 p.Lys520fs

c.1559del · rs1252879915 · VCV1395187

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

ACO2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 13 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP -1.9, phastCons 1
Overall
CADD	30.0	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 0.00534% African / African-American · 4/74,942 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,614,066 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: ACO2
Protein: p.Lys520fs
Coding: c.1559del
MANE Select: NM_001098
dbSNP: rs1252879915
Type: Deletion
Location: chr22:41524921 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44

Full ACO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACO2-related disorder

Similar variants

ACO2 p.Asn634fs Likely pathogenic ★ same condition
ACO2 p.Lys520Gln Uncertain significance ★ ⚠ same residue
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Ile275fs Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Ser239fs Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Val163Leu Uncertain significance ★★ same condition
ACO2 c.1032+1G>C 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/aco2-p-lys520fs (accessed [today's date]).

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