Is ACO2 p.Leu224= (c.670C>T) pathogenic?

ACO2 p.Leu224= (c.670C>T) is classified Benign in ACO2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 51%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with optic atrophy 9.

What condition is associated with ACO2 p.Leu224= (c.670C>T)?

ACO2 p.Leu224= (c.670C>T) is associated with optic atrophy 9, infantile cerebellar-retinal degeneration (ClinVar).

ACO2 p.Leu224=

Q: How common is ACO2 p.Leu224= (c.670C>T) in the general population?

ACO2 p.Leu224= (c.670C>T) is common (popmax 51%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.670C>T · rs1799932 · VCV128257

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 51%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

optic atrophy 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP 1.7, phastCons 1
Overall
CADD	9.842	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 51% European (non-Finnish) · 600,818/1,178,340 alleles

Filtering AF 50.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.8%

Overall 46.2% 744,894/1,610,822 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	51%	2
Ashkenazi Jewishnot grpmax-eligible	45%	2
Finnishnot grpmax-eligible	44.3%	2
Remaining individualsnot grpmax-eligible	42.6%	2
Amishnot grpmax-eligible	41.3%	2
South Asian	38.7%	3
Middle Eastern	36.7%	3
East Asian	28.2%	4
Admixed American	24.1%	4
African / African-American	15.1%	7

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.Leu224=
Coding: c.670C>T
MANE Select: NM_001098
dbSNP: rs1799932
Type: single nucleotide variant
Location: chr22:41515521 (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

optic atrophy 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: infantile cerebellar-retinal degeneration

Similar variants

ACO2 p.Leu224Pro Uncertain significance ★ ⚠ same residue
ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Gly503Ter Pathogenic ★★ same condition
ACO2 p.Ala647Gly Uncertain significance ★★ ⚠ same condition
ACO2 p.Ala768Thr Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg648Cys Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Trp Uncertain significance ★★ ⚠ 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-leu224 (accessed [today's date]).

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