Is ACO2 p.Thr64= (c.192A>C) pathogenic?

ACO2 p.Thr64= (c.192A>C) is classified Benign in ACO2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). Common (popmax 58.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with optic atrophy 9.

What condition is associated with ACO2 p.Thr64= (c.192A>C)?

ACO2 p.Thr64= (c.192A>C) is associated with optic atrophy 9, infantile cerebellar-retinal degeneration (ClinVar).

ACO2 p.Thr64=

Q: How common is ACO2 p.Thr64= (c.192A>C) in the general population?

ACO2 p.Thr64= (c.192A>C) is common (popmax 58.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.192A>C · rs137831 · VCV128256

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 58.7%, amr) — 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.52	GERP -3, phastCons 0.03
Overall
CADD	1.763	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 58.7% Admixed American · 35,187/59,948 alleles

Filtering AF 58.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 58%

Overall 24.9% 402,000/1,613,368 alleles · common exomes 356,759/1,461,416 · genomes 45,241/151,952 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	58.7%	2
East Asian	46.5%	2
South Asian	37.8%	3
African / African-American	36.2%	3
Amishnot grpmax-eligible	32.8%	3
Middle Eastern	31.8%	3
Ashkenazi Jewishnot grpmax-eligible	29.8%	3
Remaining individualsnot grpmax-eligible	27.9%	4
Finnishnot grpmax-eligible	25.9%	4
European (non-Finnish)	20.3%	5

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.Thr64=
Coding: c.192A>C
MANE Select: NM_001098
dbSNP: rs137831
Type: single nucleotide variant
Location: chr22:41507809 (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.Thr64Ser 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-thr64 (accessed [today's date]).

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