Is ACO2 p.Gly661Arg (c.1981G>A) pathogenic?

ACO2 p.Gly661Arg (c.1981G>A) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-17). AlphaMissense: likely pathogenic (0.9954); Very rare (popmax 8.47e-05%, nfe); Associated with optic atrophy.

What condition is associated with ACO2 p.Gly661Arg (c.1981G>A)?

ACO2 p.Gly661Arg (c.1981G>A) is associated with optic atrophy, optic nerve disorder (ClinVar).

How common is ACO2 p.Gly661Arg (c.1981G>A) in the general population?

ACO2 p.Gly661Arg (c.1981G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACO2 p.Gly661Arg (c.1981G>A)?

AlphaMissense predicts likely pathogenic (score 0.9954) — an in-silico prediction, not a clinical call.

ACO2 p.Gly661Arg

c.1981G>A · rs752034900 · VCV189311

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

optic atrophy

Computational evidence

Protein change
AlphaMissense	0.9954	likely pathogenic
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -14.16	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 8.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	34.0	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 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 0.000205% 3/1,461,860 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,017
European (non-Finnish)grpmax	8.47e-05%	1,180,011

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly661Arg
Coding: c.1981G>A
MANE Select: NM_001098
dbSNP: rs752034900
Type: single nucleotide variant
Location: chr22:41527315 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44
Residue 661: a UniProt-annotated variant site (in opa9)

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

Disease context

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

Also linked: optic nerve disorder

Similar variants

ACO2 p.Gly661Ala Uncertain significance ★ ⚠ same residue
ACO2 p.Gly661Glu Uncertain significance ★ same residue
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Ser669Leu Uncertain significance ★★ ⚠ same condition
ACO2 c.1482+1G>T Pathogenic ★ same condition
ACO2 p.Gln12= Likely pathogenic ★ same condition
ACO2 p.Leu74Val Conflicting classifications of pathogenicity ★ ⚠ same condition
ACO2 p.Ser66Leu 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-gly661arg (accessed [today's date]).

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