Is ACO2 p.Glu672Ala (c.2015A>C) pathogenic?

ACO2 p.Glu672Ala (c.2015A>C) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-09). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with optic atrophy 9.

What condition is associated with ACO2 p.Glu672Ala (c.2015A>C)?

ACO2 p.Glu672Ala (c.2015A>C) is associated with optic atrophy 9 (ClinVar).

How common is ACO2 p.Glu672Ala (c.2015A>C) in the general population?

ACO2 p.Glu672Ala (c.2015A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACO2 p.Glu672Ala (c.2015A>C)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

ACO2 p.Glu672Ala

c.2015A>C · rs199562524 · VCV1704307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

optic atrophy 9

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 5% in ACO2
REVEL	0.7	pathogenic-leaning
SaProt	LLR -16.16	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 11	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	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Glu672Ala
Coding: c.2015A>C
MANE Select: NM_001098
dbSNP: rs199562524
Type: single nucleotide variant
Location: chr22:41527349 (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.Glu321Lys 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

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-glu672ala (accessed [today's date]).

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