Is ACO2 p.Arg684Gln (c.2051G>A) pathogenic?

ACO2 p.Arg684Gln (c.2051G>A) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.2611); Ultra-rare (popmax 0.0217%, amr); Associated with optic atrophy 9.

What condition is associated with ACO2 p.Arg684Gln (c.2051G>A)?

ACO2 p.Arg684Gln (c.2051G>A) is associated with optic atrophy 9, infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Arg684Gln (c.2051G>A) in the general population?

ACO2 p.Arg684Gln (c.2051G>A) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about ACO2 p.Arg684Gln (c.2051G>A)?

AlphaMissense predicts likely benign (score 0.2611) — an in-silico prediction, not a clinical call.

ACO2 p.Arg684Gln

c.2051G>A · rs200345386 · VCV214022

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

optic atrophy 9

Computational evidence

Protein change
AlphaMissense	0.2611	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -10.31	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.63, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,956 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.008% 129/1,613,316 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,612
Remaining individualsnot grpmax-eligible	0.0112%	8,919
South Asian	0.00989%	10,116
European (non-Finnish)	0.00831%	12,040
African / African-American	0.00267%	37,458

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.Arg684Gln
Coding: c.2051G>A
MANE Select: NM_001098
dbSNP: rs200345386
Type: single nucleotide variant
Location: chr22:41527385 (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.Arg684Trp Uncertain significance ★★ ⚠ same residue
ACO2 p.Arg684= Likely benign ★ 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.Arg90Trp 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-arg684gln (accessed [today's date]).

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