Is ACO2 p.Glu321Lys (c.961G>A) pathogenic?

ACO2 p.Glu321Lys (c.961G>A) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.0795); Absent from gnomAD v4.1; Associated with optic atrophy 9.

What condition is associated with ACO2 p.Glu321Lys (c.961G>A)?

ACO2 p.Glu321Lys (c.961G>A) is associated with optic atrophy 9 (ClinVar).

How common is ACO2 p.Glu321Lys (c.961G>A) in the general population?

ACO2 p.Glu321Lys (c.961G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACO2 p.Glu321Lys (c.961G>A)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

ACO2 p.Glu321Lys

c.961G>A · rs2066493570 · VCV937666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

optic atrophy 9

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -2.43	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACO2
Protein: p.Glu321Lys
Coding: c.961G>A
MANE Select: NM_001098
dbSNP: rs2066493570
Type: single nucleotide variant
Location: chr22:41518501 (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

Similar variants

ACO2 p.Gly503Ter Pathogenic ★★ same condition
ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Trp Uncertain significance ★★ ⚠ same condition
ACO2 p.Gly240Ala Uncertain significance ★★ ⚠ same condition
ACO2 c.1032+17C>T Benign ★★ same condition
ACO2 c.1370+48A>G Benign ★★ same condition
ACO2 c.174-52G>T Benign ★★ same condition
ACO2 c.836-118C>T Benign ★★ 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-glu321lys (accessed [today's date]).

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