Is ACO2 p.Arg671Gln (c.2012G>A) pathogenic?

ACO2 p.Arg671Gln (c.2012G>A) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.9989); Very rare (popmax 0.00133%, afr); Associated with ACO2-related disorder.

What condition is associated with ACO2 p.Arg671Gln (c.2012G>A)?

ACO2 p.Arg671Gln (c.2012G>A) is associated with ACO2-related disorder, optic atrophy 9 (ClinVar).

How common is ACO2 p.Arg671Gln (c.2012G>A) in the general population?

ACO2 p.Arg671Gln (c.2012G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACO2 p.Arg671Gln (c.2012G>A)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

ACO2 p.Arg671Gln

c.2012G>A · rs755024692 · VCV1400671

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACO2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic · top 5% in ACO2
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -11.30	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 9.8	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	33.0	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 0.00133% African / African-American · 1/74,934 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,934
European (non-Finnish)	0.000593%	168,576

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.Arg671Gln
Coding: c.2012G>A
MANE Select: NM_001098
dbSNP: rs755024692
Type: single nucleotide variant
Location: chr22:41527346 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44
Residue 671: a binding site

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

Disease context

ACO2-related disorder

Also linked: optic atrophy 9

Similar variants

ACO2 p.Arg671Trp Conflicting classifications of pathogenicity ★ same residue
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same condition
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

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-arg671gln (accessed [today's date]).

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